SUBSTITUTED BENZO[f][l ,2,4JTRIAZOL0[4,3-a][l ,4JDIAZEPINES AS GABA A GAMMA! POSITIVE ALLOSTERIC MODULATORS

ABSTRACT

Compounds having the general formula (I)wherein R1, R2, R3, R4, R5 and X are as described herein, compositions including the compounds and methods of using the compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/217,687 filed on Mar. 30, 2021, which is entitled to the benefit ofEuropean Application No. EP20167239.1 filed on Mar. 31, 2020, thedisclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Receptors for the major inhibitory neurotransmitter, gamma-aminobutyricacid (GABA), are divided into two main classes: (1) GABA_(A) receptors,which are members of the ligand-gated ion channel superfamily and (2)GABA_(B) receptors, which are members of the G-protein linked receptorfamily. The GABA_(A) receptor complex which is a membrane-boundheteropentameric protein polymer is composed principally of α, β and γsubunits. GABA_(A) receptors are ligand-gated chloride channels and theprincipal mediators of inhibitory neurotransmission in the human brain.

There are 19 genes encoding for GABA_(A) receptor subunits that assembleas pentamers with the most common stoichiometry being two α, two β andone γ subunit. GABA_(A) subunit combinations give rise to functional,circuit, and behavioral specificity (Sieghart, 2006; Vithlani et al.,2011). GABA_(A) receptors containing the γ1 subunit (GABA_(A) γ1) are ofparticular interest due to their enriched expression in the limbicsystem (Seeburg et al., 1990; Pirker et al., 2000; Esmaeili et al.,2008; Durisic et al., 2017; Sequeira et al., 2019) and uniquephysiological and pharmacological properties (Mohler et al., 1996;Wingrove et al., 1997; Sieghart et al., 2005). The GABA_(A) γ1subunit-containing receptors, while less abundant (around 5-10% of totalexpression of GABA_(A) receptors in the brain) than γ2subunit-containing receptors exhibit an enriched brain mRNA and proteindistribution in key brain areas such as extended amygdala (central,medial, and bed nucleus of the stria terminalis), lateral septum,hypothalamus, and pallidum/nigra. These structures form theinterconnected core of a subcortical limbic circuit regulating motivatedsocial and affective behaviors. In abnormal or disease conditions,hyper-recruitment of this circuit promotes anxiety, arousal, aggression,fear and defense while inhibiting foraging and social interactions(Goossens et al., 2007; Hofmann et al., 2011; Fox et al., 2012;Martin-Santos et al., 2014; Anderson et al., 2014; Calhoon et al.,2015).

Hyperactivity in limbic cortical regions (known to form a coordinatedfunctional network with extended amygdala/hypothalamus regions) whichare key areas for processing of social and emotionally relevant stimuli,is the common hallmark of a variety of psychiatric, neurological,neurodevelopmental, neurodegenerative, mood, motivational and metabolicdisorders. In such a disease state, and given the characteristicanatomical distribution of the γ1 subunit-containing GABA_(A) receptors,a GABA_(A) γ1 positive allosteric modulator (PAM) may be an effectivetreatment as a symptomatic or disease-modifying agent.

Multiple lines of evidence suggest that an imbalance betweenexcitatory/inhibitory (E/I) neurotransmission arising from dysfunctionof GABAergic signaling system, the main inhibitory neurotransmittersystem in the brain, to be at the core of the pathogenesis a variety ofCNS disorders. Given the distribution and function of GABA_(A) γ1subunit-containing receptors in the CNS, they are very attractivetargets for restoring levels of inhibition within key brain circuits andconsequently the E/I balance in these conditions.

SUMMARY OF THE INVENTION

This invention relates to organic compounds useful for therapy orprophylaxis in a mammal, and in particular to GABA_(A) γ1 receptorpositive allosteric modulators (PAMs) for the treatment or prophylaxisof GABA_(A) γ1 receptor related diseases and diseases or conditionswhich can be treated by the modulation of GABA_(A) γ1 receptor activity,such autism spectrum disorders (ASD) targeting core symptoms andassociated comorbidities including anxiety and irritability, Angelmansyndrome, Rett syndrome, Prader-Willi syndrome, fragile-X disorder,schizophrenia including psychosis, cognitive impairment and negativesymptoms, tardive dyskinesia, anxiety, separation anxiety disorder,selective mutism, specific phobia, social anxiety disorder (socialphobia), panic disorder, agoraphobia, generalized anxiety disorder,substance/medication-induced anxiety disorder, disruptive,impulse-control and conduct disorders, Tourette's syndrome (TS),obsessive-compulsive disorder (OCD), acute stress disorder,post-traumatic stress disorder (PTSD), attention deficit hyperactivitydisorder (ADHD), sleep disorders including narcolepsy-cataplexy,neurodegenerative conditions including Parkinson's disease (PD),Huntington's chorea, Alzheimer's disease (AD), mild cognitive impairment(MCI) dementia, behavioral and psychological symptoms (BPS) inneurodegenerative conditions, multi-infarct dementia, psychosis andaggression, eating disorders including anorexia nervosa, bulimianervosa, binge eating disorder, depression and related conditionsincluding treatment-resistant depression (TRD), chronic apathy,anhedonia, chronic fatigue, seasonal affective disorder, postpartumdepression, drowsiness, sexual dysfunction, bipolar disorders, epilepsyand pain.

The present invention provides a novel compound of formula (I)

-   -   wherein    -   R¹ is selected from        -   i) H,        -   ii) C₁₋₆alkyl,        -   iii) C₁₋₆-alkoxy,        -   iv) C₁₋₆-alkoxy-C₁₋₆-alkyl,        -   v) hydroxy,        -   vi) hydroxy-C₁₋₆-alkyl,        -   vii) C₃₋₈-cycloalkyl optionally substituted by R⁷, R⁸ and            R⁹,        -   viii) amino-C₁₋₆-alkyl        -   ix) heteroaryl optionally substituted by R⁷, R⁸ and R⁹, and        -   x) heterocycloalkyl optionally substituted by R⁷, R⁸ and R⁹;    -   R² is selected from        -   i) C₁₋₆-alkyl,        -   ii) hydroxy        -   iii) hydroxy-C₁₋₆-alkyl, and        -   iv) C₁₋₆-alkoxy-C₁₋₆-alkyl;    -   R³ is selected from        -   i) Cl, and        -   ii) F;    -   X is selected from        -   i) CR, and        -   ii) N;    -   R⁶ is selected from        -   i) H,        -   ii) Cl, and        -   iii) F;    -   R⁴ is selected from        -   i) Br, and        -   ii) Cl;    -   R⁵ is selected from    -   i) C₁₋₆-alkyl,        -   ii) C₁₋₆-alkoxy,        -   iii) halogen,        -   iv) halo-C₁₋₆-alkyl,        -   v) cyano, and        -   vi) C₃₋₈-cycloalkyl;    -   R⁷, R⁸ and R⁹ are independently selected from        -   i) C₁₋₆-alkyl, and        -   ii) C₁₋₆-alkoxy;    -   or pharmaceutically acceptable salts.

Compounds described herein and their pharmaceutically acceptable saltsand esters can be used, alone or in combination with other drugs, asdisease-modifying or as symptomatic agents for the treatment orprevention of acute neurological disorders, chronic neurologicaldisorders, cognitive disorders, autism spectrum disorders (ASD),Angelman syndrome, Rett syndrome, Prader-Willi syndrome, fragile-Xdisorder, schizophrenia, tardive dyskinesia, anxiety, social anxietydisorder (social phobia), panic disorder, agoraphobia, generalizedanxiety disorder, disruptive, impulse-control and conduct disorders,Tourette's syndrome (TS), obsessive-compulsive disorder (OCD), acutestress disorder, post-traumatic stress disorder (PTSD), attentiondeficit hyperactivity disorder (ADHD), sleep disorders, Parkinson'sdisease (PD), Huntington's chorea, Alzheimer's disease (AD), mildcognitive impairment (MCI), dementia, behavioral and psychologicalsymptoms (BPS) in neurodegenerative conditions, multi-infarct dementia,agitation, psychosis, substance-induced psychotic disorder, aggression,eating disorders, depression, chronic apathy, anhedonia, chronicfatigue, seasonal affective disorder, postpartum depression, drowsiness,sexual dysfunction, bipolar disorders, epilepsy and pain.

In certain embodiments the indications treated in accordance with theinvention are anxiety, targeting social anxiety disorder (social phobia)and generalized anxiety disorder, and autism spectrum disorder (ASD),targeting core symptoms and associated comorbidities including anxietyand irritability.

ASD is a complex, heterogeneous neurodevelopmental disordercharacterized by impairments in two core domains: impairments in socialinteraction and communication, and presence of repetitive or restrictedbehaviors, interests, or activities (American Psychiatric Association2013).

No approved pharmacological treatment exists for core symptoms of socialdeficits and restricted/repetitive behaviour of ASD, while onlyinadequate therapeutic options are available for most of ASD's affectiveand physiological co-morbidities. As a result, this disorder continuesto be an area of high unmet medical need. Current approved treatmentsfor associated symptoms of ASD are limited to the antipsychotics(Risperidone and Aripiprazole) indicated for the treatment ofirritability associated with ASD symptoms. Emerging evidence suggeststhat the GABAergic system, the main inhibitory neurotransmitter systemin the brain, plays a key role in the pathophysiology of ASD (Dhosscheet al., 2002; Pizzarelli and Cherubini, 2011; Robertson et al., 2016).

Both genetic and imaging studies using positron emission tomographystudy (PET) and magnetic resonance spectroscopy (MRS) suggestalterations in GABAergic signaling in ASD. The gene encoding GABA_(A)γ1: GABRG1 is located on chromosome 4 (mouse Chr.5) in a cluster withgenes encoding α2, α4 and β1 GABA_(A) receptor subunits. Rare CNVs,including inversion of chromosome 4p12 disrupting GABRG1 have beenobserved in autistic siblings (Horike et al., 2006), as well as GABRG1loss in one case of ADHD. Mutations in 4p12 gene cluster have beenlinked to increased risk of anxiety, substance abuse and eatingdisorders—providing a link between GABRG1/4p12 and affectivedysfunction. MRS studies found altered GABA levels in ASD (Gaetz et al.,2014; Rojas et al., 2014) and in particular some recent studies showedreduced GABA and altered somatosensory function in children with ASD and(Puts et al., 2016; Robertson et al., 2016). In line with theseobservations, a reduced number of inhibitory interneurons were foundfrom postmortem tissues of ASD and TS patients (Rapanelli et al., 2017).Furthermore, reduced GABA synthesizing enzymes, glutamic aciddecarboxylase (GAD) 65 and 67 were found in parietal and cerebellarcortices of patients with autism (Fatemi et al., 2002). Strong evidencein humans points to specific dysfunction in ASD of the limbic corticalregions known to form a coordinated functional network with GABA_(A) γ1subunit-containing extended amygdala/hypothalamus regions. These areas:Cortical/lateral amygdala, Insula, PFC, and Cingulate are recognized keyfor processing of social and emotionally relevant stimuli. Whilesubcortical subnuclei that form specific partnerships with these areas,coordinating behavioural outcomes, are often difficult to study due tospatial resolution limitations, many lines of evidence point tohyper-recruitment of these cortical- to sub cortical connections in ASD.Moreover, recent high resolution studies provide a clear link betweenextended amygdala activity/functional connectivity and emotional state(Kleinhans et al., 2009, 2016; Swartz et al., 2013; Nordahl et al.,2016; Ehrlich et al., 2017; Avino et al., 2018; Ibrahim et al., 2019).Targeting such highly specific limbic subcortical regions, which exhibitsubstantial molecular and cellular diversity compared to the neocortex,will create a precision entry point for safe and specific therapeuticmodulation of ASD-affected socio-affective circuits, while avoidingbroad modulation of global brain state. Enhancement of GABA_(A) receptoractivity by non-selective BZDs have been shown to ameliorate behavioraldeficits in mouse models of ASD, however very narrow therapeutic marginswere observed due to sedation mediated by the GABA_(A) al 02 subtype(Han et al., 2012, 2014; Soto et al., 2013). These findings support thenotion that rebalancing of GABAergic transmission via GABA_(A) γ1receptors can improve symptoms in ASD without the side effects ofnon-selective benzodiazepines.

Objects of the present invention are compounds of formula (I) and theirpharmaceutically acceptable salts and esters, the preparation of theabove mentioned compounds, medicaments containing them and theirmanufacture as well as the use of the above mentioned compounds in thetreatment or prevention of diseases related to GABA_(A) γ1 receptordysfunction and diseases or conditions which can be treated by theenhancement of GABA_(A) γ1 receptor activity, such as autism spectrumdisorders (ASD), Angelman syndrome, Rett syndrome, Prader-Willisyndrome, fragile-X disorder, schizophrenia, tardive dyskinesia,anxiety, separation anxiety disorder, selective mutism, specific phobia,social anxiety disorder, panic disorder, agoraphobia, generalizedanxiety disorder, substance/medication-induced anxiety disorder,disruptive, impulse-control and conduct disorders, Tourette's syndrome(TS), obsessive-compulsive disorder (OCD), acute stress disorder,post-traumatic stress disorder (PTSD), attention deficit hyperactivitydisorder (ADHD), sleep disorders including narcolepsy-cataplexy,neurodegenerative conditions including Parkinson's disease (PD),Huntington's chorea, Alzheimer's disease (AD), mild cognitive impairment(MCI) dementia, behavioral and psychological symptoms (BPS) inneurodegenerative conditions, multi-infarct dementia, psychosis andaggression, eating disorders including anorexia nervosa, bullimianervosa, binge eating disorder, depression and related conditionsincluding treatment-resistant depression (TRD), chronic apathy,anhedonia, chronic fatigue, seasonal affective disorder, postpartumdepression, drowsiness, sexual dysfunction, bipolar disorders, epilepsyand pain.

Compounds of the present invention are selective GABA_(A) γ1 receptorpositive allosteric modulators (PAMs) as they selectively enhance thefunction of γ1-containing GABA_(A) receptors by increasing GABAergiccurrents (influx of chloride) at a given concentration (e.g. EC₂₀) ofgamma amino butyric acid (GABA). The compounds of the present inventionhave high PAM efficacy and binding selectivity for the γ1-containingsubtypes (α5γ1, α2γ1, α1γ1) relative to the □2-containing subtypes (e.g.α1γ2, α2γ2, α3γ2 and α5γ2). As such, compounds of the present inventionare strongly differentiated from classical benzodiazepine drugs such asAlprazolam, Triazolam, Estazolam, Midazolam which are selective for the□2-containing GABA_(A) subtypes and possess low affinity for theγ1-containing subtypes. Compatible with the γ1-subtypes braindistribution, selective GABA_(A) γ1 PAMs will restore GABAergicsignaling in key brain regions (e.g. extended amygdala: central, medial,and bed nucleus of the stria terminalis, lateral septum, hypothalamus,and pallidum/nigra) without the side-effects of non-selective GABA_(A)modulators (e.g. benzodiazepines).

The term “amino” denotes a —NH₂ group.

The term “amino-C₁₋₆-alkyl” denotes an C₁₋₆-alkyl group wherein one ofthe hydrogen atoms of the C₁₋₆-alkyl group has been replaced by an aminogroup. Examples of amino-C₁₋₆-alkyl include aminomethyl, aminoethyl,aminopropyl, aminomethylpropyl, aminomethylethyl and aminobutyl.

Particular example includes aminomethyl.

The term “C₁₋₆-alkoxy” denotes a group of the formula —O—R′, wherein R′is an C₁₋₆-alkyl group. Examples of C₁₋₆-alkoxy groups include methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.Particular examples are methoxy and ethoxy. More particular example ismethoxy.

The term “C₁₋₆-alkoxy-C₁₋₆-alkyl” denotes an C₁₋₆-alkyl group wherein atleast one of the hydrogen atoms of the C₁₋₆-alkyl group has beenreplaced by an C₁₋₆-alkoxy group. Exemplary C₁₋₆-alkoxy-C₁₋₆-alkylgroups include methoxymethyl, ethoxymethyl, methoxymethyl, ethoxyethyl,methoxypropyl and ethoxypropyl. Particular example includesmethoxymethyl.

The term “C₁₋₆-alkyl” denotes a monovalent linear or branched saturatedhydrocarbon group of 1 to 6 carbon atoms. Examples of C₁₋₆-alkyl includemethyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl,tert-butyl and pentyl. Particular C₁₋₆alkyl groups are methyl and ethyl.More particular example is methyl.

The term “C₃₋₈-cycloalkyl” denotes a monovalent saturated monocyclic orbicyclic hydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means aring system consisting of two saturated carbocycles having one or twocarbon atoms in common. Examples of monocyclic C₃₋₄-cycloalkyl arecyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl.Example of bicyclic C₃₋₈-cycloalkyl is spiro[3.3]heptanyl. Particularmonocyclic C₃₋₈-cycloalkyl groups are cyclopropyl and cyclobutanyl. Moreparticular monocyclic C₃₋₈-cycloalkyl group include cyclopropyl.

The term “cyano” denotes a —CN group.

The term “halo-C₁₋₆-alkyl” denotes an C₁₋₆-alkyl group wherein at leastone of the hydrogen atoms of the C₁₋₆-alkyl group has been replaced bythe same or different halogen atoms. The term“perhalo-C₁₋₆-alkyl-C₁₋₆alkyl” denotes an —C₁₋₄-alkyl-C₁₋₄-alkyl groupwhere all hydrogen atoms of the alkyl group have been replaced by thesame or different halogen atoms. Examples of halo-C₁₋₆-alkyl includefluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,difluoroethyl and trifluoroethyl. Particular halo-C₁₋₆-alkyl groupsinclude trifluoromethyl and difluoroethyl. More particularhalo-C₁₋₆-alkyl group is trifluoromethyl.

The term “halogen” and “halo” are used interchangeably herein and denotefluoro, chloro, bromo or iodo. Particular halogens include fluoro andchloro.

The term “heteroaryl” denotes a monovalent aromatic heterocyclic mono-or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4heteroatoms selected from N, O and S, the remaining ring atoms beingcarbon. Examples of heteroaryl group include pyrrolyl, furanyl, thienyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl,triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl,benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl,benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl,benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl,quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl. Particularheteroaryl groups include pyridinyl, pyrazolyl, pyrimidinyl, pyridazinyland isoxazolyl. More particular heteroaryl groups are pyrazolyl,pyrimidinyl, pyridazinyl and isoxazolyl.

The term “heterocycloalkyl” denotes a monovalent saturated or partlyunsaturated mono- or bicyclic ring system of 4 to 11 ring atoms,comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, theremaining ring atoms being carbon. Bicyclic means consisting of twocycles having one or two ring atoms in common. Examples for monocyclicsaturated heterocycloalkyl are 4,5-dihydro-oxazolyl, oxetanyl,azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl,tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl,1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oroxazepanyl. Examples for bicyclic saturated heterocycloalkyl areoxabicyclo[2.2.1]heptanyl, oxaspiro[3.3]heptanyl,8-aza-bicyclo[3.2.1]octyl, quinuclidinyl,8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl,3-oxa-9-aza-bicyclo[3.3.1]nonyl, or 3-thia-9-aza-bicyclo[3.3.1]nonyl.Examples for partly unsaturated heterocycloalkyl are dihydrofuryl,imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl.Particular heterocycloalkyl is tetrahydropyranyl.

The term “hydroxy” denotes a —OH group.

The term “hydroxy-C₁₋₆-alkyl” denotes an C₁₋₆-alkyl group wherein one ofthe hydrogen atoms of the C₁₋₆alkyl group has been replaced by a hydroxygroup. Examples of hydroxy-C₁₋₆-alkyl include hydroxymethyl,hydroxyethyl, hydroxypropyl, hydroxymethylpropyl hydroxymethylethyl andhydroxybutyl. Particular example includes hydroxymethyl.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, in particular hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleicacid, malonic acid, succinic acid, fumaric acid, tartaric acid, citricacid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid,N-acetylcystein and the like. In addition, these salts may be preparedby addition of an inorganic base or an organic base to the free acid.Salts derived from an inorganic base include, but are not limited to,the sodium, potassium, lithium, ammonium, calcium, magnesium salts andthe like. Salts derived from organic bases include, but are not limitedto salts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine, lysine,arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.Particular pharmaceutically acceptable salts of compounds of formula (I)are the hydrochloride salts, methanesulfonic acid salts and citric acidsalts.

“Pharmaceutically acceptable esters” means that compounds of generalformula (I) may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundsin vivo. Examples of such compounds include physiologically acceptableand metabolically labile ester derivatives, such as methoxymethylesters, methylthiomethyl esters and pivaloyloxymethyl esters.Additionally, any physiologically acceptable equivalents of thecompounds of general formula (I), similar to the metabolically labileesters, which are capable of producing the parent compounds of generalformula (I) in vivo, are within the scope of this invention.

The term “protecting group” (PG) denotes a group which selectivelyblocks a reactive site in a multifunctional compound such that achemical reaction can be carried out selectively at another unprotectedreactive site in the meaning conventionally associated with it insynthetic chemistry.

Protecting groups can be removed at the appropriate point. Exemplaryprotecting groups are amino-protecting groups, carboxy-protecting groupsor hydroxy-protecting groups. Particular protecting groups are thetert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz),fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) groups. Furtherparticular protecting groups are the tert-butoxycarbonyl (Boc) and thefluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting groupis the tert-butoxycarbonyl (Boc) group.

The abbreviation uM means microMolar and is equivalent to the symbol μM.

The abbreviation uL means microliter and is equivalent to the symbol μL.

The abbreviation ug means microgram and is equivalent to the symbol μg.

The compounds of formula (I) can contain several asymmetric centers andcan be present in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention the asymmetric carbonatom can be of the “R” or “S” configuration.

Also an embodiment of the present invention is a compound according toformula (I) as described herein and pharmaceutically acceptable salts oresters thereof, in particular compounds according to formula (I) asdescribed herein and pharmaceutically acceptable salts thereof, moreparticularly compounds according to formula (I) as described herein.

One embodiment of the present invention provides a compound according toformula (I) as described herein, wherein

-   -   R¹ is selected from        -   i) H,        -   ii) C₁₋₆-alkyl,        -   iii) C₁₋₆-alkoxy,        -   iv) C₁₋₆-alkoxy-C₁₋₆-alkyl,        -   v) hydroxy,        -   vi) hydroxy-C₁₋₆-alkyl,        -   vii) C₃₋₈-cycloalkyl optionally substituted by R⁷, R⁸ and            R⁹,        -   viii) amino-C₁₋₆-alkyl        -   ix) pyrazolyl optionally substituted by R⁷, R⁸ and R⁹,        -   x) pyridinyl optionally substituted by R⁷, R⁸ and R⁹,        -   xi) pyrimidinyl optionally substituted by R⁷, R⁸ and R⁹,        -   xii) pyridazinyl optionally substituted by R⁷, R⁸ and R⁹,            and        -   xiii) isoxazolyl optionally substituted by R⁷, R⁸ and R⁹;    -   R² is selected from        -   i) C₁₋₆-alkyl,        -   ii) hydroxy        -   iii) hydroxy-C₁₋₆-alkyl, and        -   iv) C₁₋₆-alkoxy-C₁₋₆-alkyl;    -   R³ is selected from        -   i) Cl, and        -   ii) F;    -   X is selected from        -   i) CR, and        -   ii) N;    -   R⁶ is selected from        -   i) H,        -   ii) Cl, and        -   iii) F;    -   R⁴ is selected from        -   i) Br, and        -   ii) Cl;    -   R⁵ is selected from        -   i) C₁₋₆-alkyl,        -   ii) C₁₋₆-alkoxy,        -   iii) halogen,        -   iv) halo-C₁₋₆-alkyl,        -   v) C₃₋₈-cycloalkyl;    -   R⁷, R⁸ and R⁹ are independently selected from        -   i) C₁₋₆-alkyl, and        -   ii) C₁₋₆-alkoxy;    -   or pharmaceutically acceptable salts.

A more particular embodiment of the present invention provides acompound of formula (I) according to claim 1, wherein

-   -   R¹ is selected from        -   i) H,        -   ii) C₁₋₆-alkyl,        -   iii) hydroxy,        -   iv) hydroxy-C₁₋₆-alkyl,        -   v) C₃₋₈-cycloalkyl optionally substituted by R⁷, R⁸ and R⁹,        -   vi) pyrazolyl optionally substituted by R⁷, R⁸ and R⁹,        -   vii) pyrimidinyl optionally substituted by R⁷, R⁸ and R⁹,        -   viii) pyridazinyl optionally substituted by R⁷, R⁸ and R⁹,            and        -   ix) isoxazolyl optionally substituted by R⁷, R⁸ and R⁹;    -   R² is selected from        -   i) C₁₋₆-alkyl,        -   ii) hydroxy        -   iii) hydroxy-C₁₋₆-alkyl, and        -   iv) C₁₋₆-alkoxy-C₁₋₆-alkyl;    -   R³ is F;    -   X is selected from        -   i) CR⁶, and        -   ii) N;    -   R⁶ is selected from        -   i) H, and        -   ii) F;    -   R⁴ is selected from        -   i) Br, and        -   ii) Cl;    -   R⁵ is selected from        -   i) C₁₋₆-alkyl,        -   ii) halogen, and        -   iii) halo-C₁₋₆-alkyl;    -   R⁷, R⁸ and R⁹ are independently selected from C₁₋₆-alkyl, or        pharmaceutically acceptable salts.

A furthermore particular embodiment of the present invention provides acompound according to formula (I) as described herein,

-   -   R¹ is C₁₋₆-alkyl;    -   R² is C₁₋₆-alkyl;    -   R³ is F;    -   X is CR⁶;    -   R⁶ is F;    -   R⁴ is Cl;    -   R⁵ is halo-C₁₋₆-alkyl;    -   or pharmaceutically acceptable salts.

Another particular embodiment of the present invention provides acompound according to formula (I) as described herein, wherein R¹ isselected from

-   -   i) H,    -   ii) C₁₋₆-alkyl,    -   iii) C₁₋₆-alkoxy,    -   iv) C₁₋₆-alkoxy-C₁₆-alkyl,    -   v) hydroxy,    -   vi) hydroxy-C₁₋₆-alkyl,    -   vii) C₃₋₈-cycloalkyl optionally substituted by R⁷, R⁸ and R⁹,    -   viii) amino-C₁-alkyl    -   ix) pyrazolyl optionally substituted by R⁷, R⁸ and R⁹,    -   x) pyridinyl optionally substituted by R⁷, R⁸ and R⁹,    -   xi) pyrimidinyl optionally substituted by R⁷, R⁸ and R⁹,    -   xii) pyridazinyl optionally substituted by R⁷, R⁸ and R⁹, and    -   xiii) isoxazolyl optionally substituted by R⁷, R⁸ and R⁹;

Another particular embodiment of the present invention provides acompound according to formula (I) as described herein, wherein R¹ isselected from

-   -   i) H,    -   ii) C₁₋₆-alkyl,    -   iii) hydroxy,    -   iv) hydroxy-C₁₋₆-alkyl,    -   v) C₃₋₈-cycloalkyl optionally substituted by R⁷, R⁸ and R⁹,    -   vi) pyrazolyl optionally substituted by R⁷, R⁸ and R⁹,    -   vii) pyrimidinyl optionally substituted by R⁷, R⁸ and R⁹,    -   viii) pyridazinyl optionally substituted by R⁷, R⁸ and R⁹, and    -   ix) isoxazolyl optionally substituted by R⁷, R⁸ and R⁹;

Another particular embodiment of the present invention provides acompound according to formula (I) as described herein, wherein R¹ isC₁₋₆-alkyl.

Another particular embodiment of the present invention provides acompound according to formula (I) as described herein, wherein R² isC₁₋₆-alkyl.

Another particular embodiment of the present invention provides acompound according to formula (I) as described herein, wherein R³ is F.

Another particular embodiment of the present invention provides acompound according to formula (I) as described herein, wherein X is CR⁶.

Another particular embodiment of the present invention provides acompound according to formula (I) as described herein, wherein R⁶ is F.

Another particular embodiment of the present invention provides acompound according to formula (I) as described herein, wherein R⁴ is Cl.

Another particular embodiment of the present invention provides acompound according to formula (I) as described herein, wherein R⁵ isselected from

-   -   i) C₁₋₆-alkyl,    -   ii) C₁₋₆-alkoxy,    -   iii) halogen,    -   iv) halo-C₁₋₆-alkyl,    -   v) C₃₋₈-cycloalkyl;

Another particular embodiment of the present invention provides acompound according to formula (I) as described herein, wherein R⁵ isselected from

-   -   i) C₁₋₆-alkyl,    -   ii) halogen, and    -   iii) halo-C₁₋₆-alkyl;

Another particular embodiment of the present invention provides acompound according to formula (I) as described herein, wherein R⁵ ishalo-C₁₋₆-alkyl.

Another particular embodiment of the present invention provides acompound according to formula (I) as described herein, wherein R⁷, R⁸and R⁹ are independently selected from C₁₋₆-alkyl.

Particular examples of a compound of formula (I) as described herein areselected from

-   (4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol;-   (4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol;-   (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one;-   (4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7,8-dichloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-8-bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   5-[(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]-3-methyl-isoxazole;-   (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one;-   (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyrimidin-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(2-methylpyrimidin-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7,8-dichloro-6-(2,6-difluorophenyl)-1-(2,6-dimethylpyrimidin-4-yl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4,8-trimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-ethyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   [(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol;-   (4S)-7-chloro-6-(2,6-difluorophenyl)-8-iodo-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   [(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanol;-   (4R)-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   [(4R)-7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol;-   (4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7-chloro-6-(2,6-difluorophenyl)-1-ethyl-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   (4S)-7-chloro-6-(2,6-difluorophenyl)-8-ethyl-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine;-   or pharmaceutically acceptable salts thereof.

Furthermore particular examples of a compound of formula (I) asdescribed herein are selected from

-   (4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine    or pharmaceutically acceptable salts thereof.

In some embodiments, the compounds of formula (I) areisotopically-labeled by having one or more atoms therein replaced by anatom having a different atomic mass or mass number. Suchisotopically-labeled (i.e., radiolabeled) compounds of formula (I) areconsidered to be within the scope of this disclosure. Examples ofisotopes that can be incorporated into the compounds of formula (I)include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,¹²³I, and ¹²⁵I, respectively. Certain isotopically-labeled compounds offormula (I), for example, those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, i.e. ³H, and carbon-14, i.e., ¹⁴C, areparticularly useful for this purpose in view of their ease ofincorporation and ready means of detection. For example, a compound offormula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99percent of a given isotope.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

Processes for the manufacture of a compound of formula (I) as describedherein are also an object of the invention.

The preparation of compounds of formula (I) of the invention may becarried out in sequential or convergent synthetic routes. Syntheses ofthe invention are shown in the following general schemes. The skillsrequired for carrying out the reactions and purifications of theresulting products are known to those skilled in the art. Thesubstituents and indices used in the following description of theprocesses have the significance given herein before unless indicated tothe contrary.

In more detail, the compounds of formula (I) can be manufactured by themethods given below, by the methods given in the examples or byanalogous methods. Appropriate reaction conditions for the individualreaction steps are known to a person skilled in the art. The reactionsequence is not limited to the one displayed in schemes 1-4, however,depending on the starting materials and their respective reactivity thesequence of reaction steps can be freely altered. Starting materials areeither commercially available or can be prepared by methods analogous tothe methods given below, by methods described in references cited in thedescription or in the examples, or by methods known in the art.

The present compounds of formula (I) and their pharmaceuticallyacceptable salts can be prepared by a process described below (Scheme1).

Scheme 1: synthesis of benzodiazepines (I) wherein all definitions areas described above and in the According to Scheme 1, a compound offormula (I) can be prepared in two steps starting from lactames(building blocks A, B, G, L, M, O, Q-U) of formula (II). Followingthionation reaction using Lawesson's reagent or P₂S₅, lactames (II) areconverted to corresponding thiolactames (III). Their reaction withhydrazides (IV) via a Pellizzari type process yields 1,2,4-triazoles ofgeneral formula (I). In alternative, 1,2,4-triazoles (I) can be obtainedby reaction between thiolactames (II) and hydrazine to form hydrazones(V) followed by treatment with triethyl orthoacetate or triethylorthoformate.

-   -   In certain embodiments of the invention where R¹ is hydroxyl        (OH), benzodiazepines of formula (I) can be obtained in two        steps according to the process described in Scheme 2. It is        widely accepted that 3-hydroxy-1,2,4-triazoles are existing as        two tautomeric forms and in this invention they will be        represented exclusively in their most stable form (triazolones).        To this end, hydrazones (V) can be reacted with        1,1′-carbonyldiimidazole (CDI) to yield triazolones of        formula (I) (Scheme 2).

The synthesis of building blocks (A, B, G, L, M, O, Q-U) of formula (II)is highlighted in Scheme 3. Commercially available2-amino-6-chlorobenzoic acid or 2-amino-6-bromobenzoic acid can beheated in acetic anhydride to form5-chloro-2-methyl-3,1-benzoxazin-4-one and5-bromo-2-methyl-3,1-benzoxazin-4-one, respectively. Grignard ororganolithium reagents of formula (VI) (prepared by metalation reactionfrom corresponding aryl bromide or via kinetic deprotonation) can bereacted with benzoxazin-4-ones (electrophiles) at controlledtemperatures to provide ketones of formula (VII). Following N-acetamidehydrolysis under acidic conditions (HCl), compounds of formula (VII) areconverted into anilines of formula (VIII). Conveniently, at thisjunction, the halogen at R⁵ can be installed by treatment withN-chlorosuccinimide (NCS), N-bromosuccinimide (NBS) or N-iodosuccinimide(NIS) to yield intermediates of formula (IX). Final thermal cyclisationreaction with ethyl 2-aminoacetate hydrochloride in pyridine yields thedesired benzodiazepines (II), presumably via formation of imineintermediate (X).

In further embodiments of the invention, where R² is alkyl orsubstituted alkyl, an alternative process is envisaged and detailed inScheme 4.

In such a case, compounds of formula (XI) can be prepared by amidecoupling reaction between anilines (IX) and N-Boc protected L-aminoacids upon exposure to phosphoryl chloride (POCl₃), or by other methodsknown to those skilled in the art. Removal of N-Boc protecting group canbe effected with mineral acids (e.g. HCl) or organic acids (e.g.trifluoroacetic acid) to yield amines of formula (XII). Finalintramolecular condensation reaction promoted by acidic media (e.g.silica or acetic acid) and heat (80-110° C.) provides the desiredbenzodiazepine building blocks (A-U) of formula (II). Notably, in theprocesses described in Scheme 1 and 4, racemization at the chiral centeroccurs to a different extent (20-100%) depending on specific reactionconditions adopted. As a result, chiral purification (e.g. by HPLC orSFC) of final derivatives of formula (I) is required to obtain finalderivatives with enantiomeric excess (ee) above 97%.

Also an embodiment of the present invention is a process to prepare acompound of formula (I) as defined above comprising the reaction of acompound of formula (III) with a compound of formula (IV) in a solvent,particularly an alcohol, such as butan-1-ol, and at temperature betweenroom temperature and reflux of solvent, particularly at reflux ofsolvent.

wherein R¹, R², R³, R⁴ and R⁵ are as defined herein.

Also an object of the present invention is a compound according toformula (I), more particularly compounds of formula (I), as describedherein for use as a therapeutically active substance.

Likewise an object of the present invention is a pharmaceuticalcomposition comprising a compound according to formula (I), moreparticularly compounds of formula (I), as described herein and atherapeutically inert carrier.

A particular embodiment of the present invention is a compound accordingto formula (I) or pharmaceutically acceptable salts thereof, asdescribed herein for use in the treatment or prophylaxis, moreparticularly for use the treatment, of Alzheimer's disease, mildcognitive impairment (MCI), age-related cognitive decline, negativeand/or cognitive symptoms associated with schizophrenia, bipolardisorders, autism spectrum disorder (ASD), Angelman syndrome, Rettsyndrome, Prader-Willi syndrome, epilepsy, post-traumatic stressdisorder (PTSD), amyotrophic lateral sclerosis (ALS), fragile-Xdisorder, more particularly autism spectrum disorder (ASD), Angelmansyndrome, Alzheimer's disease, negative and/or cognitive symptomsassociated with schizophrenia and post-traumatic stress disorder (PTSD).

The present invention also relates to the use of a compound according toformula (I) or pharmaceutically acceptable salts thereof, moreparticularly compounds of formula (I), as described herein for thepreparation of a medicament for the treatment or prophylaxis, moreparticularly the treatment, of Alzheimer's disease, mild cognitiveimpairment (MCI), age-related cognitive decline, negative and/orcognitive symptoms associated with schizophrenia, bipolar disorders,autism spectrum disorder (ASD), Angelman syndrome, Rett syndrome,Prader-Willi syndrome, epilepsy, post-traumatic stress disorder (PTSD),amyotrophic lateral sclerosis (ALS), fragile-X disorder, moreparticularly autism spectrum disorder (ASD), Angelman syndrome,Alzheimer's disease, negative and/or cognitive symptoms associated withschizophrenia and post-traumatic stress disorder (PTSD).

Also an object of the invention is a method for the treatment orprophylaxis, more particularly the treatment, of Alzheimer's disease,mild cognitive impairment (MCI), age-related cognitive decline, negativeand/or cognitive symptoms associated with schizophrenia, bipolardisorders, autism spectrum disorder (ASD), Angelman syndrome, Rettsyndrome, Prader-Willi syndrome, epilepsy, post-traumatic stressdisorder (PTSD), amyotrophic lateral sclerosis (ALS), fragile-Xdisorder, more particularly autism spectrum disorder (ASD), Angelmansyndrome, Alzheimer's disease, negative and/or cognitive symptomsassociated with schizophrenia and post-traumatic stress disorder (PTSD),which method comprises administering an effective amount of a compoundaccording to formula (I), more particularly compounds of formula (I), asdescribed herein.

Also an embodiment of the present invention are compounds of formula(I), more particularly compounds of formula (I), as described herein,when manufactured according to any one of the described processes.

ASSAY PROCEDURES Membrane Preparation and Binding Assay forγ1-Containing GABA_(A) Subtypes

The affinity of compounds at GABA_(A) γ1 subunit-containing receptorswas measured by competition for [³H]RO7239181 (67.3 Ci/mmol; Roche)binding to membranes from HEK293F cells (ThermoFisher R79007) expressinghuman (transiently transfected) receptors of composition α5β2γ1, α2β2γ1,α1β2γ1. For better protein expression of the α2 subunit-containingreceptors, the 28 amino acid long signal peptide (Met1 to Ala28) of thehuman GABA_(A) α2 subunit was substituted by the 31 amino acid longsignal peptide (Met1 to Ser31) of human GABA_(A) α5 subunit.

Harvested pellets from HEK293F cells expressing the different GABA_(A)receptor subtypes were resuspended in Mannitol Buffer pH 7.2-7.4(Mannitol 0.29M, Triethylamine 10 mM, Acetic acid 10 mM, EDTA 1 mM plusprotease inhibitors (20 tablets Complete, Roche Diagnostics Cat. No. 05056 489 001 per liter)), washed two times and then resuspended at 1:10to 1:15 dilution in the same buffer. Cell disruption was performed bystirring the suspension in a Parr vessel #4637 at 435 psi for 15minutes, and then the suspensions were centrifuged at 1000×g for 15minutes at 4° C. (Beckman Avanti J-HC; rotor JS)-4.2). The supernatant(S1) was transferred in a 21 Schott flask and the pellet (P1) wasresuspended with Mannitol Buffer up to 175 ml. The resuspended pelletwas transferred into a 250 ml Corning centrifugal beaker and centrifugedat 1500×g for 10 minutes at 4° C. (Beckman Avanti J-HC; rotor JS)-4.2).The supernatant (S1) was then transferred in the 21 Schott flask and thepellet was discarded. The supernatants (S1) were centrifuged in 500 mlBeckman polypropylene centrifugal beaker at 15,000×g for 30 minutes at4° C. (Beckman Avanti J-20 XP; rotor JLA-10.500). The pellet (P2) wasresuspended with Mannitol Buffer 1:1 and frozen at −80° C. Thesupernatant (S2) was centrifuged in 100 ml Beckman polypropylenecentrifugal tubes at 48000×g for 50 minutes at 40° C. (Beckman AvantiJ-20 XP; rotor JA-18). The supernatant (S3) was discarded and the pellet(P3) was resuspended with 1:1 Mannitol Buffer. The P2 and P3 proteinconcentration was determined with the BIORAD Standard assay method withbovine serum albumin as standard and measured on the NANO-Drop 1000. Themembrane suspension was aliquots (500 μl per tube) and stored at −80° C.until required.

Membrane homogenates were resuspended and polytronised (Polytron PT1200EKinematica AG) in Potassium Phosphate 10 mM, KCl 100 mM binding bufferat pH 7.4 to a final assay concentration determined with a previousexperiment.

Radioligand binding assays were carried out in a volume of 200 □L(96-well plates) which contained 100 μL of cell membranes, [³H]RO7239181at a concentration of 1.5 nM (α5β2γ1) or 20-30 nM (α1β2γ1, 2β2γ1) andthe test compound in the range of [0.3-10000]×10⁻⁹ M. Nonspecificbinding was defined by 10×10⁻⁶ (α5β2γ1) and 30×10⁻⁶ M RO7235136 andtypically represented less than 5% (α5β2γ1) and less than 20% (α1β2γ1,α2β2γ1) of the total binding. Assays were incubated to equilibrium for 1hour at 4° C. and then, membranes were filtered onto unifilter (96-wellwhite microplate with bonded GF/C filters preincubated 20-50 minutes in0.3% Polyethylenimine) with a Filtermate 196 harvester (PackardBioScience) and washed 4 times with cold Potassium Phosphate 10 mM pH7.4, KCl 100 mM binding buffer. After drying, filter-retainedradioactivity was detected by liquid scintillation counting. K, valueswere calculated using Excel-Fit (Microsoft) and are the means of twodeterminations.

The compounds of the accompanying examples were tested in the abovedescribed assays, and the preferred compounds were found to possess a K,value for the displacement of [³H]RO7239181 from GABA_(A) γ1subunit-containing receptors (e.g. α5β2γ1, α2β2γ1, α1β2γ1) of 100 nM orless. Most preferred are compounds with a Ki (nM)<50. Representativetest results, obtained by the above described assay measuring bindingaffinity to HEK293 cells expressing human (h) receptors, are shown inthe Table 1.

Preparation of [³H]RO7239181,6-chloro-5-(2,6-difluorophenyl-7-methyl-1-(tritritiomethyl)-3H-1,4-benzodiazepin-2-onea)6-Chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

A microwave tube was charged with7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one(building block A (see infra), 450 mg, 1.17 mmol), trimethylboroxine(205 mg, 228 μL, 1.63 mmol), potassium carbonate (242 mg, 1.75 mmol) andtetrakis(triphenylphosphine)palladium (0) (67.4 mg, 58.4 μmol). Degassed1,4-dioxane (8.1 mL) and H₂O (2.7 ml) were added then the vial wascapped. The suspension was reacted in microwave at 130° C. for 30 min togive complete conversion. The mixture was evaporated, treated with sat.aq. NaHCO₃ (20 mL) and extracted with EtOAc (2×20 mL).

The organic layers were dried over Na₂SO₄, filtered and solvents wereevaporated. The residue was purified by flash chromatography (silicagel, 40 g, eluted with CH₂Cl₂/EtOAc in heptane 10% to 40% to 70%) togive the title compound (344 mg, 92%) as light yellow solid. MS (ESI):321.1 ([M+H]⁺).

b)6-Chloro-5-(2,6-difluorophenyl)-7-methyl-1-(tritritiomethyl)-3H-1,4-benzodiazepin-2-one

To a solution of [³H]methyl nosylate (1.85 GBq, 50 mCi, 0.61 μmol) inTHF (200 μL) were added the N-desmethyl precursor6-chloro-5-(2,6-difluorophenyl)-7-methyl-1,3-dihydro-1,4-benzodiazepin-2-one(0.43 mg, 1.34 μmol) dissolved in THE (200 μL) and 10 equivalents ofsodium tert-butylate (0.5 M in THF, 13.4 μmol). After stirring for 4 hat room temperature the reaction mixture was treated with H₂O,evaporated, and the crude product was purified by HPLC (X-Terra PrepRP-18, 10×150 mm, MeCN/H₂O (containing 5% of MeCN) 40:60.4 ml/min, 230nm). The pure tritium-labeled compound was isolated by solid phaseextraction (Sep-Pak Plus C18) and eluted from the cartridge as ethanolicsolution to yield 1.6 GBq (43.2 mCi) of the target compound in >99%radio-chemical purity and a specific activity of 2.49 TBq/mmol (67.3Ci/mmol) as determined by mass spectrometry (MS). The identity of thelabeled compound was confirmed by HPLC (by co-injecting the unlabeledreference standard) and by MS.

MS: m/z=335 [M(H)+H]⁺ (16%), 337 [M(³H)+H]⁺ (0%), 339 [M(³H₂)+H]⁺ (16%),341 [M(³H₃)+H]⁺ (68%).

Membrane Preparation and Binding Assay for γ2-Containing GABA_(A)Subtypes

The affinity of compounds at GABA_(A) γ2 subunit-containing receptorswas measured by competition for [³H]Flumazenil (81.1 Ci/mmol; Roche)binding to HEK293F cells expressing human (transiently transfected)receptors of composition α1β3γ2.

Harvested pellets from HEK293F cells expressing the different GABA_(A)γ2 receptor subtypes were resuspended in Mannitol Buffer pH 7.2-7.4 andprocessed as described above for the cells expressing the GABA_(A) γ1subunit-containing receptors.

Radioligand binding assays were carried out in a volume of 200 μL(96-well plates) which contained 100 μL of cell membranes,[³H]Flumazenil at a concentration of 1 nM and the test compound in therange of 0.1×10⁻⁹ to 30×10⁻⁶ M. Nonspecific binding was defined by 10⁻⁵M Diazepam and typically represented less than 5% of the total binding.Assays were incubated to equilibrium for 1 hour at 4° C. and harvestedonto GF/C uni-filters (Packard) by filtration using a Packard harvesterand washing with ice-cold wash buffer (50 mM Tris; pH 7.5). Afterdrying, filter-retained radioactivity was detected by liquidscintillation counting. K_(i) values were calculated using Exel-Fit(Microsoft) and are the means of two determinations.

The compounds of the accompanying examples were tested in the abovedescribed assay, and the preferred compounds were found to possess largeK, value for displacement of [³H]Flumazenil from the α1β3γ2 subtype ofthe human GABA_(A) receptor of 100 nM or above. Most preferred arecompounds with a K_(i) α1β3γ2 (nM)>300. In a preferred embodiment thecompounds of the invention are binding selective for the γ1subunit-containing GABA_(A) receptors relative to γ2 subunit-containingGABA_(A) receptors. In particular, compounds of the present inventionhave γ2/γ1 selectivity ratio defined as “K_(i) α1β3γ2 (nM)/K_(i) α2βγ1(nM)” (above 10-fold, or LogSel defined as “Log[K_(i) α1β3γ2 (nM)/K_(i)α2βγ1 (nM)]” above 1. Representative test results, obtained by the abovedescribed assay measuring binding affinity to HEK293 cells expressinghuman (h) receptors, are shown in the Table 1 below.

TABLE 1 Ki Ki Ki Ki h-GABA_(A) h-GABA_(A) h-GABA_(A) h-GABA_(A) γ2/γ1Ex- α5β2γ1 α2β2γ1 α1β2γ1 α1β3γ2 Selectivity ample (nM) (nM) (nM) (nM)Ratio LogSel 30 2.6 43.6 65.0 582.2 13.3 1.13 31 2.8 41.0 39.7 706.817.3 1.24 32 1.3 10.5 33.3 1030.2 98.2 1.99 35 8.4 78.6 639.9 2801.535.7 1.55 51 0.8 4.9 9.0 393.0 79.5 1.90 52 1.1 5.7 10.2 637.6 112.42.05 53 1.1 3.0 14.4 246.4 82.0 1.91 56 0.8 4.6 3.8 850.5 186.8 2.27 635.6 39.4 332.6 4081.1 103.5 2.02 64 0.5 13.2 11.5 602.2 45.8 1.66 66 8.097.8 231.3 3277.5 33.5 1.53 67 3.2 26.5 188.4 1420.0 53.5 1.73 68 7.038.8 359.2 1062.4 27.4 1.44 73 2.0 8.8 23.5 768.3 87.5 1.94 74 2.6 17.328.3 1865.2 107.6 2.03 75 0.8 5.3 8.3 202.0 38.0 1.58 76 3.6 24.9 44.6530.5 21.3 1.33 80 3.0 23.6 42.6 1070.2 45.3 1.66 81 4.3 36.3 100.81561.9 43.0 1.63 82 0.6 10.6 12.8 260.8 24.6 1.39 83 2.7 23.2 127.7852.7 36.8 1.57 84 6.5 71.3 97.1 1205.3 16.9 1.23 85 3.3 53.0 63.6 705.213.3 1.12 86 1.4 4.4 5.9 860.0 195.1 2.29 87 2.1 7.5 8.0 531.5 70.9 1.8588 3.6 10.9 34.5 1453.3 133.6 2.13 89 4.3 77.0 106.2 1464.1 19.0 1.28 921.8 21.9 48.3 2229.2 102.0 2.01 93 3.1 39.1 85.1 5955.5 152.1 2.18 942.0 8.0 10.3 608.7 76.4 1.88 95 1.5 14.2 24.7 465.8 32.7 1.51 96 3.013.9 27.9 473.3 34.1 1.53 97 2.5 27.1 33.6 425.2 15.7 1.19 98 4.4 72.057.6 1464.6 20.3 1.31 99 3.2 55.4 63.4 2016.9 36.4 1.56 100 3.4 19.834.0 288.0 14.6 1.16 101 1.0 26.4 14.3 494.7 18.8 1.27 102 0.8 8.0 6.6277.6 34.7 1.54 103 5.4 50.4 49.8 3377.7 67.0 1.83 105 20.1 99.3 ND7337.0 73.9 1.87 106 4.3 71.3 ND 7635.3 107.1 2.03 107 3.0 68.3 ND3532.0 51.8 1.71 108 2.0 47.0 ND 2369.5 50.4 1.70 109 3.7 65.8 ND 753.511.5 1.06

Functional Expression of GABA_(A) Receptors:

Xenopus Oocytes Preparation

Xenopus laevis oocytes at maturation stages V-VI were used for theexpression of cloned mRNA encoding GABA_(A) receptor subunits. Oocytesready for RNA micro-injection were bought from Ecocyte, Castrop-Rauxel,Germany and stored in modified Barth's medium (composition in mM: NaCl88, KCl 1, NaHCO₃ 2.4, HEPES 10, MgSO₄ 0.82, CaNO₃ 0.33, CaCl₂ 0.33,pH=7.5) at 20° C. until the experiment.

Xenopus Oocytes Microinjection

Oocytes were plated in 96-well plates for microinjection using theRoboinject automated instrument (MultiChannelSystems, Reutlingen,Germany). Approximately 50 nL of an aqueous solution containing the RNAtranscripts for the subunits of the desired GABA_(A) receptor subtypewas injected into each oocyte. RNA concentrations ranged between 20 and200 pg/μL/subunit and were adjusted in pilot experiments to obtain GABAresponses of a suitable size and a maximal effect of Flunitrazepam,Triazolam and Midazolam, reference benzodiazepine positive allostericmodulators (PAM) at the GABA_(A) receptor benzodiazepine (BZD) bindingsite. Oocytes were kept in modified Barth's medium (composition in mM:NaCl 88, KCl 1, NaHCO₃ 4, HEPES 10, MgSO₄ 0.82, CaNO₃ 0.33, CaCl₂ 0.33,pH=7.5) at 20° C. until the experiment.

Electrophysiology

Electrophysiological experiments were performed using the Roboocyteinstrument (MultiChannelSystems, Reutlingen, Germany) on days 3 to 5after the micro-injection of mRNA. During the experiment the oocyteswere constantly superfused by a solution containing (in mM) NaCl 90, KCl1, HEPES 5, MgCl₂ 1 CaCl₂ 1 (pH 7.4). Oocytes were impaled by two glassmicroelectrodes (resistance: 0.5-0.8 MΩ) which were filled with asolution containing KCl 1M+K-acetate 1.5 M and voltage-clamped to −80mV. The recordings were performed at room temperature using theRoboocyte two-electrode voltage clamp system (Multichannelsystem). Afteran initial equilibration period of 1.5 min GABA was added for 1.5 min ata concentration evoking approximately 20% of a maximal current response(EC₂₀). After another rest interval of 2.5 min GABA was again addedevoking a response of similar amplitude and shape. 0.5 min after theonset of this second GABA application the test compound, at aconcentration corresponding to approximatively 30-fold its K_(i) α2β2γ1,was added while GABA was still present. Current traces were recorded ata digitization rate of 10 Hz during and shortly before and after theGABA application.

Each compound and concentration was tested on at least 3 oocytes.Different oocytes were used for different compound concentrations. Thereference PAMs, Flunitrazepam, Triazolam and Midazolam, potentiated theGABA-induced current in α2βγ1 GABA_(A) receptor subtype expressingoocytes by approximatively 60%.

Data Analysis

For the analysis, the digitized current traces of the first and secondGABA response were superimposed and, if necessary, rescaled to equalmaximal amplitudes. The ratio between the two responses during the timeinterval of test compound application was calculated point by point. Theextremum of the resulting “ratio trace” was taken as the efficacy (“Foldincrease”) of the compound expressed as “% modulation of GABA EC₂₀”(100*(Fold increase−1)).

The results are shown in Table 2.

TABLE 2 Fold increase Ki h-GABA-A h-GABA_(A) α2β2γ1 α2β2γ1 oocyte @Efficacy Example (nM) 30-fold Ki (GABA)% 30 43.6 1.57 57 31 41.0 1.74 7432 10.5 2.05 105 35 78.6 2.08 108 51 4.9 1.56 56 52 5.7 2.00 100 53 3.01.32 32 56 4.6 1.78 78 63 39.4 9.91 891 64 13.2 1.74 74 66 97.8 2.43 14367 26.5 1.69 69 68 38.8 2.09 109 73 8.8 2.05 105 74 17.3 1.62 62 75 5.31.57 57 76 24.9 1.52 52 80 23.6 1.59 59 81 36.3 1.46 46 82 10.6 1.45 4583 23.2 2.02 102 84 71.3 3.03 203 85 53.0 2.14 114 86 4.4 1.80 80 87 7.51.42 42 88 10.9 2.05 105 89 77.0 1.88 88 92 21.9 1.92 92 93 39.1 2.69169 94 8.0 1.47 47 95 14.2 1.53 53 96 13.9 1.52 52 97 27.1 2.48 148 9872.0 2.07 107 99 55.4 2.35 135 100 19.8 1.64 64 101 26.4 2.19 119 1028.0 1.89 89 103 50.4 2.23 123 105 99.3 1.75 75 106 71.3 2.21 121 10768.3 2.47 147 108 47.0 1.94 94 109 65.8 3.30 230

Reference Compounds

The reference compounds (classical marketed benzodiazepines) and theirstructural analogues listed below were also tested for their affinitytowards the GABA_(A) receptor α1β2γ1 and α2β2γ1 subtypes as well as inthe GABA_(A) receptor α1β3γ2 subtype. The results are shown in Table 3.

TABLE 3 Ki Ki Ki h-GABA_(A) h-GABA_(A) h-GABA_(A) γ2/γ1 α1β2γ1 α2β2γ1α1β3γ2 Selectivity Example (nM) (nM) (nM) Ratio LogSel Alprazolam 59233945 19.6 0.0050 −2.3 Triazolam 44.2 46.2 1.5 0.032 −1.5 Estazolam ND3182 28.4 0.0089 −2.0 Midazolam 1153.2 737.7 5.0 0.0068 −2.2 RE-A ND32.1 5.6 0.18 −0.74 RE-B ND 68.4 15.6 0.23 −0.64 RE-C ND 626.7 5.80.0092 −2.0 RE-D ND 453.9 1005.5 2.215 0.35 Example 30 65.0 43.6 582.213.3 1.1 Example 51 9.0 4.9 393.0 80 1.9 Example 86 5.9 4.4 860.0 1952.3

The compounds of formula (I) and their pharmaceutically acceptable saltscan be used as medicaments (e.g. in the form of pharmaceuticalpreparations). The pharmaceutical preparations can be administeredinternally, such as orally (e.g. in the form of tablets, coated tablets,dragees, hard and soft gelatin capsules, solutions, emulsions orsuspensions), nasally (e.g. in the form of nasal sprays), rectally (e.g.in the form of suppositories) or topical ocularly (e.g. in the form ofsolutions, ointments, gels or water soluble polymeric inserts). However,the administration can also be effected parenterally, such asintramuscularly, intravenously, or intraocularly (e.g. in the form ofsterile injection solutions).

The compounds of formula (I) and their pharmaceutically acceptable saltscan be processed with pharmaceutically inert, inorganic or organicadjuvants for the production of tablets, coated tablets, dragees, hardgelatin capsules, injection solutions or topical formulations Lactose,corn starch or derivatives thereof, talc, stearic acid or its salts etc.can be used, for example, as such adjuvants for tablets, dragees andhard gelatin capsules.

Suitable adjuvants for soft gelatin capsules, are, for example,vegetable oils, waxes, fats, semi-solid substances and liquid polyols,etc.

Suitable adjuvants for the production of solutions and syrups are, forexample, water, polyols, saccharose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water,alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural orhardened oils, waxes, fats, semi-solid or liquid polyols, etc.

Suitable adjuvants for topical ocular formulations are, for example,cyclodextrins, mannitol or many other carriers and excipients known inthe art.

Moreover, the pharmaceutical preparations can contain preservatives,solubilizers, viscosity-increasing substances, stabilizers, wettingagents, emulsifiers, sweeteners, colorants, flavorants, salts forvarying the osmotic pressure, buffers, masking agents or antioxidants.They can also contain still other therapeutically valuable substances.

The dosage can vary in wide limits and will, of course, be fitted to theindividual requirements in each particular case. In general, in the caseof oral administration a daily dosage of about 0.1 mg to 20 mg per kgbody weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g.about 300 mg per person), divided into preferably 1-3 individual doses,which can consist, for example, of the same amounts, should it beappropriate. In the case of topical administration, the formulation cancontain 0.001% to 15% by weight of medicament and the required dose,which can be between 0.1 and 25 mg in can be administered either bysingle dose per day or per week, or by multiple doses (2 to 4) per day,or by multiple doses per week It will, however, be clear that the upperor lower limit given herein can be exceeded when this is shown to beindicated.

-   -   Preparation of Pharmaceutical Compositions Comprising Compounds        of the Invention:

Tablets of the following composition are manufactured in the usualmanner:

mg/tablet Ingredient 5 25 100 500 Compound of formula I  5  25 100 500Lactose Anhydrous DTG 125 105  30 150 Sta-Rx 1500  6  6  6  60Microcrystalline Cellulose  30  30  30 450 Magnesium Stearate  1  1  1 1 Total 167 167 167 831

Manufacturing Procedure

-   -   1. Mix ingredients 1, 2, 3 and 4 and granulate with purified        water.    -   2. Dry the granules at 50° C.    -   3. Pass the granules through suitable milling equipment.    -   4. Add ingredient 5 and mix for three minutes; compress on a        suitable press.

Capsules of the following composition are manufactured:

mg/capsule Ingredient 5 25 100 500 Compound of formula I  5  25 100 500Hydrous Lactose 159 123 148 — Corn Starch  25  35  40  70 Talk  10  15 10  25 Magnesium Stearate  1  2  2  5 Total 200 200 300 600

Manufacturing Procedure

-   -   1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30        minutes.    -   2. Add ingredients 4 and 5 and mix for 3 minutes.    -   3. Fill into a suitable capsule.

A compound of formula I lactose and corn starch are firstly mixed in amixer and then in a comminuting machine. The mixture is returned to themixer; the talc is added thereto and mixed thoapproximatively. Themixture is filled by machine into suitable capsules, e.g. hard gelatincapsules.

Injection solutions of the following composition are manufactured:

Ingredient mg/injection solution. Compound of formula I  3 PolyethyleneGlycol 400 150 acetic acid q.s. ad pH 5.0 water for injection solutionsad 1.0 ml

The invention is illustrated hereinafter by Examples, which have nolimiting character.

In case the preparative examples are obtained as a mixture ofenantiomers, the pure enantiomers can be obtained by methods describedherein or by methods known to those skilled in the art, such as e.g.chiral chromatography or crystallization.

EXAMPLES Building Block A7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one

a) 5-chloro-2-methyl-3,1-benzoxazin-4-one

A solution of 2-amino-6-chlorobenzoic acid (250 g, 1.46 mol) in aceticanhydride (1250 mL) was stirred at 140° C. for 2 h. The reaction mixturewas concentrated in vacuo. The resulting crude residue was suspended inethyl acetate (1000 mL), stirred for 30 min, filtered and dried in vacuoto afford the title compound (238 g, 84%) as a grey solid. ¹H NMR(DMSO-d₆, 400 MHz): δ: 7.80 (app t, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz,1H), 7.49 (d, J=7.6 Hz, 1H), 2.36 (s, 3H).

b) N-[3-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide

To a solution of 5-chloro-2-methyl-3,1-benzoxazin-4-one (100 g, 511.2mmol) and 2-bromo-1,3-difluorobenzene (118.4 g, 613.5 mmol) intetrahydrofuran (1000 mL) was added dropwise i-PrMgCl LiCl (1.3 M, 500mL, 650 mmol) at −70° C. under nitrogen. The mixture was allowed to warmup to room temperature within 1 h, quenched with saturated aqueousammonium chloride (1500 mL) and extracted with ethyl acetate (2×1500mL). The organic phase was washed with brine (2000 mL), dried oversodium sulfate and concentrated in vacuo. The residue was suspended inethyl acetate (150 mL). The resulting suspension was stirred at roomtemperature for 20 min, filtered and dried in vacuo to afford the titlecompound (113 g, 71%) as an off-white solid. ¹H NMR (DMSO-d₆, 400 MHz):δ: 9.85 (s, 1H), 7.65-7.45 (m, 1H), 7.40 (t, J=7.2 Hz, 1H), 7.38-7.34(m, 2H), 7.16 (t, J=8.8 Hz, 2H), 1.85 (s, 3H).

c) (2-amino-6-chloro-phenyl)-(2,6-difluorophenyl)methanone

To a solution of N-[3-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide(113 g, 364.9 mmol) in ethanol (250 mL) was added aqueous hydrochloricacid (12 M, 200 mL). The reaction mixture was stirred at 100° C. for 1h, then diluted with ethyl acetate (1100 mL). The organic phase waswashed with water (1100 mL), saturated aqueous sodium bicarbonate (1100mL) and brine (1100 mL), dried over sodium sulfate and concentrated invacuo. Petroleum ether (120 mL) was added to the crude and thesuspension was stirred at room temperature for 20 min. The solid wasfiltered and dried to afford the title compound (88 g, 90%) as a yellowsolid. ¹H NMR (DMSO-d₆, 400 MHz): δ: 7.62-7.56 (m, 1H), 7.21-7.15 (m,3H), 6.83 (d, J=7.6 Hz, 1H), 6.74 (s, 2H), 6.58 (d, J=7.6 Hz, 1H).

d) (6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone

To a solution of (2-amino-6-chloro-phenyl)-(2,6-difluorophenyl)methanone(88.0 g, 328.8 mmol) in dichloromethane (225 mL) andN,N-dimethylformamide (225 mL) was added 1-bromopyrrolidine-2,5-dione(64.4 g, 362 mmol) at 0° C. The reaction mixture was stirred at 30° C.for 1 h. The mixture was diluted with dichloromethane (600 mL) andwashed with water (500 mL) and brine (4×500 mL), dried over sodiumsulfate and concentrated in vacuo. The residue was purified bychromatography (silica, petroleum ether/ethyl acetate, 1:0 to 2:1). Thesolid was suspended in petroleum ether (200 mL) and stirred at roomtemperature for 20 min. The suspension was filtered and the solid wasdried in vacuo to afford the title compound (96.0 g, 84%) as a yellowsolid. MS: 345.9 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 347.8 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br,³⁷Cl}M+H]⁺), ESI pos.

e)7-bromo-6-chloro-5-(2,6-difluorophenyl-1,3-dihydro-1,4-benzodiazepin-2-one

To a solution of(6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone (25.0 g,72.1 mmol) in pyridine (625 mL) was added ethyl 2-aminoacetatehydrochloride (70.5 g, 505 mmol). The reaction mixture was stirred at135° C. for 36 h. The reaction mixture was concentrated in vacuo toremove pyridine. The residue was diluted with ethyl acetate (2000 mL)and washed with HCl (1.0 M, 3×1500 mL), water (2000 mL) and brine(2×1000 mL), dried over sodium sulfate, filtered and concentrated invacuo. The crude product was purified by flash column chromatography(silica, petroleum ether/ethyl acetate 10:1 to 2:1) to afford the titlecompound (10.1 g, 12%) as an off-white solid. MS: 385.0 ([{⁷⁹Br,³⁵Cl}M+H]⁺), ESI pos.

Building Block B

7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-onea) N-[3-chloro-2-(2-fluorobenzoyl)phenyl]acetamide

To a solution of 5-chloro-2-methyl-3,1-benzoxazin-4-one (20.0 g, 102.3mmol) and 1-bromo-2-fluorobenzene (17.9 g, 102.3 mmol) intetrahydrofuran (600 mL) at −70° C. was added dropwise n-BuLi intetrahydrofuran (2.5 M, 49 mL, 123 mmol). The reaction mixture wasstirred at −60° C. for 1 h, then quenched with aqueous ammonium chloride(200 mL). The aqueous layer was extracted with tetrahydrofuran (2×250mL) and ethyl acetate (2×250 mL). The combined organic phase was washedwith brine (200 mL), dried over sodium sulfate and concentrated invacuo. Purification by flash column chromatography (silica, petroleumether/ethyl acetate 20:1 to 3:1) afforded the title compound (21 g, 70%)as a white solid. MS: 292.3 ([M+H]⁺), ESI pos.

b) (2-amino-6-chloro-phenyl)-(2-fluorophenyl)methanone

In analogy to experiment of building block A c,N-[3-chloro-2-(2-fluorobenzoyl)phenyl]acetamide was converted into thetitle compound (10 g, 58%) which was obtained as a yellow solid. MS:250.1 ([M+H]⁺), ESI pos.

c) (6-amino-3-bromo-2-chloro-phenyl)-(2-fluorophenyl)methanone

In analogy to experiment of building block A d,(2-amino-6-chloro-phenyl)-(2-fluorophenyl)methanone was converted intothe title compound (32.4 g, 70%) which was obtained as a yellow solid.MS: 327.9 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 330.0 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br,³⁷Cl}M+H]⁺), ESI pos.

d)7-bromo-6-chloro-5-(2-fluorophenyl-1,3-dihydro-1,4-benzodiazepin-2-one

To a solution of(6-amino-3-bromo-2-chloro-phenyl)-(2-fluorophenyl)methanone (35.0 g,98.3 mmol) in pyridine (210 mL) was added ethyl 2-aminoacetatehydrochloride (96.0 g, 688 mmol) at 90° C. The reaction mixture wasstirred at 110° C. for 16 h. The reaction mixture was cooled down toroom temperature and most of pyridine was removed in vacuo. The residuewas diluted with ethyl acetate (1250 mL). The organic phase was washedwith aqueous HCl (1.0 M, 1250 mL), water (500 mL) and brine (1000 mL),dried over sodium sulfate, filtered and concentrated in vacuo. The crudewas purified by flash column chromatography (silica, petroleumether/ethyl acetate 1:0, 25:1, 1:1). The product was dissolved in ethylacetate (15 mL). Petroleum ether (45 mL) was added dropwise to get awhite slurry. The solid was collected by filtration and dried in vacuoto afford the title compound (30.4 g, 39%) as an off-white solid. MS:367.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 368.9 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺),ESI pos.

Building Block G(rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

a) (rac)-tert-butylN-[2-[4-bromo-3-chloro-2-(2-fluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

To a solution of(6-amino-3-bromo-2-chloro-phenyl)-(2-fluorophenyl)methanone (2.0 g, 6.09mmol) and 2-(tert-butoxycarbonylamino)propanoic acid (1.73 g, 9.13 mmol)in pyridine (20 mL) was added phosphoryl chloride (1.22 g, 7.98 mmol)slowly at −5° C. The reaction mixture was stirred at −5° C. for 1 h,before being slowly poured into water (200 mL) and extracted with ethylacetate (2×100 mL). The combined organic phase was washed with brine(2×50 mL), dried over sodium sulfate and concentrated in vacuo. Theresidue was purified by flash column chromatography (petroleumether/ethyl acetate 5:1) to afford the title compound (2.95 g, 97%) as ayellow solid. MS: 399.1 ([{⁷⁹Br, ³⁵Cl}M-C₄H₈—CO₂+H]⁺), 401.0 ([{⁸¹Br,³⁵Cl or ⁷⁹Br, ³⁷Cl}M−C₄H₈—CO₂+H]⁺), ESI pos.

b)(rac)-2-amino-N-[4-bromo-3-chloro-2-(2-fluorobenzoyl)phenyl]propanamide

To a solution of (rac)-tert-butylN-[2-[4-bromo-3-chloro-2-(2-fluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate(2.9 g, 5.8 mmol) in dichloromethane (14.5 mL) was slowly addedhydrochloric acid (4.0 M in dioxane, 14.5 mL, 58.0 mmol). The reactionmixture was stirred at 25° C. for 2 h. Saturated aqueous sodiumbicarbonate was added slowly until pH>8, then the mixture was extractedwith dichloromethane (3×100 mL). The combined organic phase was washedwith brine (100 mL), dried over sodium sulfate and concentrated in vacuoto afford the title compound (2.2 g, 92%) as a yellow oil. MS: 399.0([{⁷⁹Br, ³⁵Cl}M+H]⁺), 401.0 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

c)(rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

To a solution of(rac)-2-amino-N-[4-bromo-3-chloro-2-(2-fluorobenzoyl)phenyl]propanamide(2.2 g, 5.5 mmol) in ethanol (20 mL) was added acetic acid (4 mL). Thereaction mixture was stirred at 80° C. for 16 h, then concentrated invacuo. The formed crystals were filtered, purified by trituration withethyl acetate (15 mL), then collected by filtration and dried in vacuoto afford the title compound (1.6 g, 76%) as a yellow solid. MS: 381.0([{⁷⁹Br, ³⁵Cl}M+H]⁺), 383.0 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Building Block L(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

a) tert-butylN-[(1S)-2-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

In analogy to experiment of building block G a,(6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone using(2S)-2-(tert-butoxycarbonylamino)propanoic acid was converted into thetitle compound (1.50 g, 98%) which was obtained as a yellow solid. MS:418.7 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M−C₄H₈—CO₂+H]⁺), 540.7 ([{⁸¹Br, ³⁵Clor ⁷⁹Br, ³⁷Cl}M+Na]⁺), ESI pos.

b)(2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]propanamide

In analogy to experiment of building block G b, tert-butylN-[(1S)-2-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamatewas converted into the title compound (1.1 g, 94%) which was obtained asa yellow oil, which was used as such in the following step withoutfurther characterization.

c)(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

To a solution of(2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]propanamide(960 mg, 2.30 mmol) in toluene (9.19 mL) was added silica (138 mg, 2.30mmol). The reaction mixture was stirred at 90° C. for 15 h, thenconcentrated in vacuo. The residue was purified by flash columnchromatography (petroleum ether/ethyl acetate 3:1) to afford the titlecompound (920 mg, 95%) as a yellow solid. MS: 399.1 ([{⁷⁹Br,³⁵Cl}M+H]⁺), 401.1 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Building Block M(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

a) tert-butylN-[(1S)-2-[3,4-dichloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

In analogy to experiment of building block G a,(6-amino-2,3-dichloro-phenyl)-(2,6-difluorophenyl)methanone using(2S)-2-(tert-butoxycarbonylamino)propanoic acid was converted into thetitle compound (5.0 g, 64%) which was obtained as a yellow foam. Thecrude was used as such in the following step without furthercharacterization.

b)(2S)-2-amino-N-[3,4-dichloro-2-(2,6-difluorobenzoyl)phenyl]propanamide

In analogy to experiment of building block G b, tert-butylN-[(1S)-2-[3,4-dichloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamatewas converted into the title compound (3.6 g, 91%) which was obtained asa yellow oil. MS: 373.0 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESI pos.

c)(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

In analogy to experiment of building block L c,(2S)-2-amino-N-[3,4-dichloro-2-(2,6-difluorobenzoyl)phenyl]propanamidewas converted into the title compound (3.20 g, 93%) which was obtainedas a yellow foam. MS: 355.0 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESI pos.

Building Block O(3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

a) tert-butylN-[(1S)-2-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

In analogy to experiment of building block G a,N-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)phenyl]acetamide using(2S)-2-(tert-butoxycarbonylamino)propanoic acid was converted into thetitle compound (8.6 g, 67%) as a white solid. MS: 456.0 ([{³⁵Cl,³⁵Cl}M+H]⁺), ESI pos.

b)(2S)-2-amino-N-[3,4-dichloro-2(3-fluoropyridine-2-carbonyl)phenyl]propanamide

In analogy to experiment of building block G b, tert-butylN-[(1S)-2-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)anilino]-1-methyl-2-oxo-ethyl]carbamatewas converted into the title compound (6.6 g, 100%) which was obtainedas a yellow solid. MS: 356.0 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESI pos.

c)(3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

In analogy to experiment of building block L c,(2S)-2-amino-N-[3,4-dichloro-2-(3-fluoropyridine-2-carbonyl)phenyl]propanamidewas converted into the title compound (5.5 g, 88%) which was obtained asa yellow solid. MS: 338.0 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESI pos.

Building Block Q(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

a) N-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide

In analogy to experiment of building block A d,N-(3-bromo-2-(2,6-difluorobenzoyl)phenyl)acetamide using1-chloropyrrolidine-2,5-dione was converted into the title compound(10.1 g, 70%) which was obtained as a light yellow solid. MS: 388.0([{⁷⁹Br, ³⁵Cl}M+H]⁺), 390.1 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

b) (6-amino-2-bromo-3-chloro-phenyl)-(2,6-difluorophenyl)methanone

In analogy to experiment of building block A c,N-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)phenyl]acetamide wasconverted into the title compound (8.2 g, 92%) which was obtained as ayellow solid. MS: 346.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 348.0 ([{⁸¹Br, ³⁵Cl or⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

c) tert-butylN-[(1S)-2-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

In analogy to experiment of building block G a,(6-amino-2-bromo-3-chloro-phenyl)-(2,6-difluorophenyl)methanone using(2S)-2-(tert-butoxycarbonylamino)propanoic acid was converted into thetitle compound (8.64 g, 69%) which was obtained as a yellow solid. MS:515.2 ([{⁷⁹Br, ³⁵Cl}M−H]⁻), 517.1 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M−H]⁻),ESI neg.

d)(2S)-2-amino-N-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)phenyl]propanamide

In analogy to experiment of building block G b, tert-butylN-[(1S)-2-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)anilino]-1-methyl-2-oxo-ethyl]carbamatewas converted into the title compound (6.27 g, 90%) which was obtainedas a light brown oil. MS: 417.1 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 419.0 ([{⁸¹Br,³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

e)(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

In analogy to experiment of building block L c,(2S)-2-amino-N-[3-bromo-4-chloro-2-(2,6-difluorobenzoyl)phenyl]propanamidewas converted into the title compound (3.98 g, 68%) which was obtainedas a yellow solid. MS: 399.1 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 401.0 ([{⁸¹Br, ³⁵Clor ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Building Block R(3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

a) tert-butylN-[(1S)-2-[4-bromo-3-chloro-2(3-fluoropyridine-2-carbonyl)anilino]-1-methyl-2-oxo-ethyl]carbamate

In analogy to experiment of building block G a,(6-amino-3-bromo-2-chloro-phenyl)-(3-fluoro-2-pyridyl)methanone using(2S)-2-(tert-butoxycarbonylamino)propanoic acid was converted into thetitle compound (1.4 g, 97%) which was obtained as a yellow foam. Thecrude was used as such in the following step without furthercharacterization.

b)(2S)-2-amino-N-[4-bromo-3-chloro-2-(3-fluoropyridine-2-carbonyl)phenyl]propanamide

In analogy to experiment of building block G b, tert-butylN-[(1S)-2-[4-bromo-3-chloro-2-(3-fluoropyridine-2-carbonyl)anilino]-1-methyl-2-oxo-ethyl]carbamatewas converted into the title compound (1.1 g, 98%) which was obtained asa yellow oil. The crude was used as such in the following step withoutfurther characterization.

c)(3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

In analogy to experiment of building block L c,(2S)-2-amino-N-[4-bromo-3-chloro-2-(3-fluoropyridine-2-carbonyl)phenyl]propanamidewas converted into the title compound (430 mg, 40%) which was obtainedas a yellow solid. MS: 381.9 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 383.9 ([{⁸¹Br, ³⁵Clor ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Building Block S(3S)-6-chloro-5-(2,6-difluorophenyl)-7-iodo-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

a) tert-butylN-[(1S)-2-[3-chloro-2-(2,6-difluorobenzoyl)-4-iodo-anilino]-1-methyl-2-oxo-ethyl]carbamate

In analogy to experiment of building block G a,(6-amino-2-chloro-3-iodo-phenyl)-(2,6-difluorophenyl)methanone using(2S)-2-(tert-butoxycarbonylamino)propanoic acid was converted into thetitle compound (5.8 g, 81%) which was obtained as a yellow solid. MS:465.0 ([M−C₄H₈—CO₂+H]⁺), 509.0 ([M−C₄H₈+H]⁺), ESI pos.

b)(2S)-2-amino-N-[3-chloro-2-(2,6-difluorobenzoyl)-4-iodo-phenyl]propanamide

In analogy to experiment of building block G b, tert-butylN-[(1S)-2-[3-chloro-2-(2,6-difluorobenzoyl)-4-iodo-anilino]-1-methyl-2-oxo-ethyl]carbamatewas converted into the title compound (4.7 g, 99%) which was obtained asa yellow solid. The crude was used as such in the following step withoutfurther characterization.

c)(3S)-6-chloro-5-(2,6-difluorophenyl)-7-iodo-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one

In analogy to experiment of building block L c,(2S)-2-amino-N-[3-chloro-2-(2,6-difluorobenzoyl)-4-iodo-phenyl]propanamidewas converted into the title compound (3.8 g, 94%) which was obtained asa yellow solid. MS: 446.8 ([M+H]⁺), ESI pos.

Building Block T(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one

a) tert-butylN-[(1S)-1-[[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]carbamoyl]propyl]carbamate

In analogy to experiment of building block G a,(6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone using(2S)-2-(tert-butoxycarbonylamino)butanoic acid was converted into thetitle compound (1.08 g, 68%) which was obtained as a yellow solid. MS:433.1 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M−C₄H₈—CO₂+H]⁺), 477.1 ([{⁸¹Br, ³⁵Clor ⁷⁹Br, ³⁷Cl}M−C₄H₈+H]⁺), ESI pos.

b)(2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]butanamide

In analogy to experiment of building block G b, tert-butylN-[(1S)-1-[[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]carbamoyl]propyl]carbamatewas converted into the title compound (730 mg, 90%) which was obtainedas a yellow oil. MS: 433.0 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

c)(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one

In analogy to experiment of building block L c,(2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]butanamidewas converted into the title compound (650 mg, 97%) which was obtainedas a light brown foam. MS: 414.9 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESIpos.

Building Block U(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-one

a) tert-butylN-[(1S)-2-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)anilino]-1-(methoxymethyl)-2-oxo-ethyl]carbamate

In analogy to experiment of building block G a,(6-amino-3-bromo-2-chloro-phenyl)-(2,6-difluorophenyl)methanone using(2S)-2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid was convertedinto the title compound (4.3 g, 85%) which was obtained as a yellowsolid. The crude was used as such in the following step without furthercharacterization.

b)(2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]-3-methoxy-propanamide

In analogy to experiment of building block G b, tert-butylN-[(1S)-2-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)anilino]-1-(methoxymethyl)-2-oxo-ethyl]carbamatewas converted into the title compound (3.0 g, 96%) which was obtained asa yellow oil. MS: 447.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 449.1 ([{⁸¹Br, ³⁵Cl or⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

c)(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl-3-(methoxymethyl-1,3-dihydro-1,4-benzodiazepin-2-one

In analogy to experiment of building block L c,(2S)-2-amino-N-[4-bromo-3-chloro-2-(2,6-difluorobenzoyl)phenyl]-3-methoxy-propanamidewas converted into the title compound (1.9 g, 78%) which was obtained asa white solid. The crude was used as such in the following step withoutfurther characterization. MS: 429.1 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 431.1 ([{⁸¹Br,³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 30(4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a)(rac)-7-bromo-6-chloro-5-(2-fluorophenyl-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

To a suspension of(rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one(building block G, 500 mg, 1.31 mmol) in toluene (8.33 mL) at roomtemperature was added Lawesson's reagent (635 mg, 1.57 mmol). Thereaction mixture was stirred at 110° C. for 1 h, before beingconcentrated in vacuo. The crude material was purified by flash columnchromatography (silica, 15-25% ethyl acetate in heptane) to afford thetitle compound (820 mg, 91%) which was obtained as a yellow solid. Thecrude was used as such in the following step without furthercharacterization.

b)(rac)-8-bromo-7-chloro-6-(2-fluorophenyl-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

To a solution of(rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione(240 mg, 0.600 mmol) in butan-1-ol (3.2 mL) was added formohydrazide(108 mg, 1.81 mmol). The reaction mixture was stirred at 120° C. for 16h. The mixture was diluted with dichloromethane (20 mL), washed withwater (20 mL), brine (20 mL), dried over sodium sulfate and concentratedin vacuo. The residue was purified by preparative HPLC (TFA) to affordthe title compound (250 mg, 100%) which was obtained as a white solid.MS: 404.8 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 406.7 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br,³⁷Cl}M+H]⁺), ESI pos.

c)(4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(rac)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(254 mg, 0.630 mmol) was purified by SFC (Chiralcel OJ-3, 0.05%diethylamine in methanol, 5-40%) affording:

(−)-enantiopure (S)-title compound (88.1 mg) as a white solid. MS: 404.8([{⁷⁹Br, ³⁵Cl}M+H]⁺), 406.8 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

(+)-enantiopure (R)-title compound (80.4 mg) as a white solid. MS: 404.9([{⁷⁹Br, ³⁵Cl}M+H]⁺), 406.8 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 318-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol

a)7-bromo-6-chloro-5-(2,6-difluorophenyl-1,3-dihydro-1,4-benzodiazepin-2-thione

To a suspension of7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one(building block A, 6.7 g, 17.4 mmol) in toluene (167 mL) at roomtemperature was added Lawesson's reagent (8.43 g, 20.9 mmol). Thereaction mixture was stirred at 120° C. for 1.5 h, before being dilutedwith ethyl acetate (400 mL). The organic layer was washed with water(300 mL) and brine (300 mL), dried over sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by flash columnchromatography (silica, 15-30% ethyl acetate in heptane) to afford thetitle compound (6.98 g, 100%) as a yellow solid. MS: 400.8 ([{⁷⁹Br,³⁵Cl}M+H]⁺), 402.9 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

b)8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,7-bromo-6-chloro-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-thioneusing formohydrazide was converted into the title compound (2.4 g, 32%)which was obtained as a white solid. MS: 409.1 ([{⁷⁹Br, ³⁵Cl}M+H]⁺),411.1 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

c)8-bromo-7-chloro-6-(2,6-difluorophenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol

To a solution of sodium bis(trimethylsilyl)amide (1.0 M intetrahydrofuran, 0.37 mL, 0.370 mmol) in tetrahydrofuran (5 mL) wasadded8-bromo-7-chloro-6-(2,6-difluorophenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(100.0 mg, 0.240 mmol) at −65° C. The mixture was stirred at −65° C. for30 min, then 2-(benzenesulfonyl)-3-phenyl-oxaziridine (97 mg, 0.370mmol) was added. The reaction mixture was stirred at −65° C. for 2 h,before being quenched by addition of saturated aqueous ammoniumchloride. The aqueous phase was extracted with ethyl acetate (2×10 mL).The combined organic layers were washed with brine (2×30 mL), filteredand concentrated in vacuo. The residue was purified by preparative HPLC(Boston Prime C18, 0.1% trifluoroacetic acid in water/acetonitrile)followed by chiral-HPLC (Daicel Chiralcel OJ-H, methanol) to afford thetitle compound (30 mg, 29%) as a white solid. MS: 424.9 ([{⁷⁹Br,³⁵Cl}M+H]⁺), 426.8 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 32(4S)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a)(rac)-8-bromo-7-chloro-6-(2-fluorophenyl-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(rac)-7-bromo-6-chloro-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing pyridazine-3-carbohydrazide was converted into the title compound(220 mg, 75%) which was obtained as a white solid. MS: 482.9 ([{⁷⁹Br,³⁵Cl}M+H]⁺), 484.8 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

b)(4S)-8-bromo-7-chloro-6-(2-fluorophenyl-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

(rac)-8-bromo-7-chloro-6-(2-fluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(220 mg, 0.450 mmol) was purified by SFC (Chiralcel OJ-3, 0.05%diethylamine in methanol, 5-40%), followed by lyophilization affording:

(−)-enantiopure (S)-title compound (64.3 mg) as a white solid. MS: 483.1([{⁷⁹Br, ³⁵Cl}M+H]⁺), 485.1 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

(+)-enantiopure (R)-title compound (61.4 mg) as a white solid. MS: 483.1([{⁷⁹Br, ³⁵Cl}M+H]⁺), 485.1 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 358-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol

a)7-bromo-6-chloro-5-(2-fluorophenyl-1,3-dihydro-1,4-benzodiazepine-2-thione

In analogy to experiment of example 30 a,7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-onewas converted into the title compound (390 mg, 54%) which was obtainedas a yellow solid. The crude was used as such in the following stepwithout further characterization.

b)8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,7-bromo-6-chloro-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thioneusing pyridazine-3-carbohydrazide was converted into the title compound(294 mg, 73%) which was obtained as a white solid. MS: 469.1 ([{⁷⁹Br,³⁵Cl}M+H]⁺), 471.1 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

c)[8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate

To a solution of8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(100 mg, 0.21 mmol) in acetic acid (2 mL) was added iodine (27 mg, 0.11mmol), potassium acetate (42 mg, 0.43 mmol) and potassium persulfate (58mg, 0.21 mmol). The reaction mixture was heated to 90° C. for 12 h,before being quenched by addition of saturated aqueous Na₂SO₃ (10 mL).The mixture was extracted with ethyl acetate (30 mL). The organic layerwas washed with water (10 mL), dried over sodium sulfate andconcentrated in vacuo. The residue was purified by flash columnchromatography (silica, dichloromethane/methanol 100:1 to 80:1) toafford the title compound (55 mg, 49%) as a white solid. MS: 526.9([{⁸¹Br, ³⁵Cl}M+H]⁺), 528.9 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

d)8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-ol

To a solution of[8-bromo-7-chloro-6-(2-fluorophenyl)-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetate (55 mg, 0.10 mmol) in ethanol (2.75 mL) was added sodiumcarbonate (22 mg, 0.21 mmol). The reaction mixture was stirred at roomtemperature for 4 h, then filtered and concentrated in vacuo. Theresidue was purified by preparative TLC (dichloromethane/methanol),followed by preparative HPLC (Shim-pack C18, 0.225% trifluoroacetic acidin water/acetonitrile) and lyophilized to afford the title compound(13.1 mg, 26%) as a white solid. MS: 485.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 487.0([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁵Cl}M+H]⁺), ESI pos.

Example 51(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a)(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

In analogy to experiment of example 30 a,(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one(building block L) was converted into the title compound (410 mg, % %)which was obtained as a yellow solid. MS: 415.1 ([{⁷⁹Br, ³⁵Cl}M+H]⁺),417.0 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

b)(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing formohydrazide was converted after chiral purification into the(−)-enantiopure (S)-title compound (66 mg, 43%) which was obtained as awhite solid. MS: 423.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 425.1 ([{⁸¹Br, ³⁵Cl or⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 52(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a)(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

In analogy to experiment of example 30 a,(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one(building block M) was converted into the title compound (4.2 g, 90%)which was obtained as a yellow solid. The crude was used as such in thefollowing step without further characterization.

b)(4S)-7,8-dichloro-6-(2,6-difluorophenyl-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing pyrimidine-4-carbohydrazide was converted after chiralpurification into the (−)-enantiopure (S)-title compound (71.6 mg, 31%)which was obtained as a white solid. MS: 456.9 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESIpos.

Example 53(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing 1-methylpyrazole-4-carbohydrazide was converted after chiralpurification into the (−)-enantiopure (S)-title compound (60.8 mg, 29%)which was obtained as a white solid. MS: 459.1 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESIpos.

Example 56(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing pyridazine-3-carbohydrazide was converted after chiralpurification into the (−)-enantiopure (S)-title compound (80.0 mg, 21%)which was obtained as a white solid. MS: 457.0 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESIpos.

Example 63(4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a)(3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

In analogy to experiment of example 30 a,(3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one(building block O) was converted into the title compound (2.56 g, 67%)which was obtained as a light yellow solid. MS: 354.0 ([{³⁵Cl,³⁵Cl}M+H]⁺), ESI pos.

b)(4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thionewas converted after chiral purification into the (+)-enantiopure(S)-title compound (8.8 mg, 2%) which was obtained as a white solid. MS:440.1 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESI pos.

Example 64(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one

a)(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-onehydrazone

To a solution of(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione(400 mg, 1.08 mmol) in tetrahydrofuran (8.7 mL) was added at roomtemperature hydrazine monohydrate (109 mg, 104 μl, 2.15 mmol). Themixture was stirred at room temperature for 2 h under argon. Thesuspension was concentrated in vacuo to give a light yellow solid thatwas treated with methyl tert-butyl ether (2 mL) and diluted with pentane(4 mL). The mixture was scratched to give a suspension that was stirredfor 10 min. The solid was filtered, washed with pentane (2×3 mL) anddried in high vacuo to afford the title compound (300 mg, 75%) which wasobtained as a yellow solid. MS: 369.1 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESI pos.

b)(4S)-7,8-dichloro-6-(2,6-difluorophenyl-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one

To a solution of(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-onehydrazone (250 mg, 0.68 mmol) in tetrahydrofuran (6 mL) was added atroom temperature 1,1′-carbonyldiimidazole (132 mg, 0.81 mmol). Thereaction mixture was stirred at 70° C. for 5 h, then concentrated invacuo. The residue was purified by SFC (Chiralcel OJ-3, 0.05%diethylamine in methanol, 5 to 40%) to give the (−)-enantiopure(S)-title compound (141.2 mg, 53%) which was obtained as a white solid.MS: 395.1 ({³⁵Cl, ³⁵Cl}[M+H]⁺), ESI pos.

Example 66(4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing pyrimidine-4-carbohydrazide was converted after chiralpurification into the (+)-enantiopure (S)-title compound (17 mg, 3%)which was obtained as a white solid. MS: 440.1 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESIpos.

Example 67(4S)-7,8-dichloro-6-(3-fluoro-2-pyridyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing 1-methylpyrazole-4-carbohydrazide was converted after chiralpurification into the (+)-enantiopure (S)-title compound (86 mg, 46%)which was obtained as a white solid. MS: 442.2 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESIpos.

Example 68(4S)-7,8-dichloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing cyclopropanecarbohydrazide was converted after chiral purificationinto the (+)-enantiopure (S)-title compound (123 mg, 21%) which wasobtained as a white solid. MS: 402.1 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESI pos.

Example 73(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(pyridazin-3-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine

a)(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

In analogy to experiment of example 30 a,(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one(building block Q) was converted into the title compound (2.72 g, 77%)which was obtained as a yellow powder. MS: 415.1 ([{⁷⁹Br, ³⁵Cl}M+H]⁺),417.0 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

b)(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl-4-methyl-1-pyridazin-3-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing pyridazine-3-carbohydrazide was converted after chiralpurification into the (−)-enantiopure (S)-title compound (24 mg, 20%)which was obtained as a white solid. MS: 501.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺),503.1 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 74(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-pyrimidin-4-yl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing pyrimidine-4-carbohydrazide was converted after chiralpurification into the (−)-enantiopure (S)-title compound (13 mg, 11%)which was obtained as a white solid. MS: 501.1 ([{⁷⁹Br, ³⁵Cl}M+H]⁺),503.0 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 75(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing acetohydrazide was converted after chiral purification into the(−)-enantiopure (S)-title compound (36 mg, 23%) which was obtained as awhite solid. MS: 437.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 439.1 ([{⁸¹Br, ³⁵Cl or⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 76(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing 1-methylpyrazole-4-carbohydrazide was converted after chiralpurification into the (−)-enantiopure (S)-title compound (13 mg, 11%)which was obtained a white solid. MS: 503.1 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 505.1([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁵Cl}M+H]⁺), ESI pos.

Example 80(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing acetohydrazide was converted after chiral purification into the(−)-enantiopure (S)-title compound (13 mg, 11%) which was obtained as awhite solid. MS: 436.9 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 438.9 ([{⁸¹Br, ³⁵Cl or⁷⁹Br, ³⁵Cl}M+H]⁺), ESI pos.

Example 81(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(1-methylpyrazol-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing 1-methylpyrazole-3-carbohydrazide was converted after chiralpurification into the (−)-enantiopure (S)-title title compound (38 mg,26%) which was obtained as a white solid. MS: 503.0 ([{⁷⁹Br,³⁵Cl}M+H]⁺), 505.1 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 82(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing acetohydrazide was converted after chiral purification into the(−)-enantiopure (S)-title compound (62.3 mg, 19%) which was obtained asa white solid. MS: 393.0 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESI pos.

Example 83(4S)-8-bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a)(3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione

In analogy to experiment of example 30 a,(3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-one(building block R) was converted into the title compound (720 mg, 46%)which was obtained as a yellow solid. MS: 398.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺),400.1 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

b)(4S)-8-bromo-7-chloro-1-cyclopropyl-6-(3-fluoro-2-pyridyl-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing cyclopropanecarbohydrazide was converted after chiral purificationinto the (+)-enantiopure (S)-title compound (38 mg, 11%) which wasobtained as a light yellow solid. MS: 446.1 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 448.0([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 84(4S)-8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing formohydrazide was converted after chiral purification into the(+)-enantiopure (S)-title compound (38 mg, 12%) which was obtained as alight yellow solid MS: 406.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 408.1 ([{⁸¹Br, ³⁵Clor ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 85(4S)-8-bromo-7-chloro-6-(3-fluoro-2-pyridyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-7-bromo-6-chloro-5-(3-fluoro-2-pyridyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing acetohydrazide was converted after chiral purification into the(+)-enantiopure (S)-title compound (31 mg, 8%) which was obtained as awhite solid MS: 420.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 422.0 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br,³⁷Cl}M+H]⁺), ESI pos.

Example 86(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a) 6-methylpyridazine-3-carbohydrazide

A solution of ethyl 6-methylpyridazine-3-carboxylate (3.71 g, 22.3 mmol)in methanol (40 mL) was heated to 60° C. After 10 min,hydrazine-monohydrate (1.62 mL, 33.5 mmol) was carefully added and thereaction mixture was allowed to cool down to room temperature. Followingup the addition of diethyl ether (60 mL), the reaction mixture wascooled down to 0° C. After 2 hours, the resulting suspension wasfiltered through a sintered funnel. The collected solid was washed withdiethyl ether and dried under high vacuum to afford the title compound(1.4 g, 41%) which was obtained as an off-white powder. MS: 153.1([M+H]⁺), ESI pos.

b)(4S)-7,8-dichloro-6-(2,6-difluorophenyl-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing 6-methylpyridazine-3-carbohydrazide was converted after chiralpurification into the (−)-enantiopure (S)-title compound (52.6 mg, 44%)which was obtained as a white solid. MS: 471.1 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESIpos.

Example 875-[(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]-3-methyl-isoxazole

a) 3-methyl-1,2-didehydroisoxazole-5-carbohydrazide

In analogy to experiment of example 86 a, methyl3-methyl-1,2-didehydroisoxazole-5-carboxylate was converted into thetitle compound (800 mg, 74%) which was obtained as a white solid. MS:142.1 ([M+H]⁺), ESI pos.

b)5-[(4S)-7,8-dichloro-6-(2,6-difluorophenyl-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]-3-methyl-isoxazole

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing 3-methyl-1,2-didehydroisoxazole-5-carbohydrazide was convertedafter chiral purification into the (−)-enantiopure (S)-title compound(54.1 mg, 31%) which was obtained as a white solid. MS: 460.1 ([{³⁵Cl,³⁵Cl}M+H]⁺), ESI pos.

Example 88(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyridazin-3-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing 6-methylpyridazine-3-carbohydrazide was converted after chiralpurification into the (−)-enantiopure (S)-title compound (30 mg, 24%)which was obtained as a white solid MS: 515.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺),517.0 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 89(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl)-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one

a)(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-onehydrazone

In analogy to experiment of example 64 a,(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thionewas converted into the title compound (40 mg, 20%) which was obtained asa powder. MS: 413.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 415.0 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br,³⁷Cl}M+H]⁺), ESI pos.

b)(4S)-7-bromo-8-chloro-6-(2,6-difluorophenyl-4-methyl-2,4-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-one

In analogy to experiment of example 64 b,(3S)-6-bromo-7-chloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepin-2-onehydrazone was converted after chiral purification into the(−)-enantiopure (S)-title compound (12 mg, 28%) which was obtained as awhite solid. MS: 439.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 441.1 ([{⁸¹Br, ³⁵Cl or⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 92(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a)(3S)-6-chloro-5-(2,6-difluorophenyl-3-methyl-7-(trifluoromethyl-1,3-dihydro-1,4-benzodiazepin-2-one

A solution of(3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one(building block S, 500 mg, 1.12 mmol), iodocopper (426 mg, 2.24 mmol),hexamethylphosphoramide (2.5 mL, 1.12 mmol) and methyl2,2-difluoro-2-fluorosulfonyl-acetate (645 mg, 3.36 mmol) inN,N-dimethylformamide (5 mL) was stirred at 70° C. for 16 h. Methyl2,2-difluoro-2-fluorosulfonyl-acetate (430 mg, 2.24 mmol) and iodocopper(213 mg, 1.12 mmol) were added and the reaction mixture stirred at 70°C. for additional 4 h. The mixture was diluted with ethyl acetate (150mL), washed with saturated aqueous ammonium chloride (80 mL) and theorganic layer was filtered through a sintered funnel. The filtrate waswashed with water (50 mL) and brine (50 mL), dried over sodium sulfateand concentrated in vacuo. The crude was purified by flash columnchromatography (silica, petroleum ether/ethyl acetate, 20:1 to 1:1) toafford the title compound (550 mg, 127%) which was obtained as a darkred oil. MS: 389.0 ([M+H]⁺), ESI pos.

b)(3S)-6-chloro-5-(2,6-difluorophenyl-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione

In analogy to experiment of example 30 a,(3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepin-2-onewas converted into the title compound (400 mg, 77%) which was obtainedas a yellow solid. MS: 405.0 ([M+H]⁺), ESI pos.

c)(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thioneusing acetohydrazide was converted after chiral purification into the(−)-enantiopure (S)-title compound (63.5 mg, 32%) which was obtained asa white solid. MS: 427.1 ([M+H]⁺), ESI pos.

Example 93(4S)-7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a)(4S)-7-chloro-6-(2,6-difluorophenyl-8(1-ethoxyvinyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

To a suspension of(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(example 75, 210.0 mg, 0.480 mmol) and tributyl(1-ethoxyvinyl)tin(346.57 mg, 0.960 mmol) in N,N-dimethylformamide (2.1 mL) was addedtetrakis(triphenylphosphine)palladium(0) (56.42 mg, 0.050 mmol). Thereaction mixture was stirred at 80° C. for 1 h. The mixture was dilutedwith dichloromethane (2×20 mL), washed with water (20 mL) and brine (20mL), dried over sodium sulfate and concentrated in vacuo. The residuewas purified by flash column chromatography (silica, petroleumether/ethyl acetate 10:1, dichloromethane/methanol 80:1) to afford thetitle compound (300 mg, 98%) which was obtained as a colorless oil. MS:429.1 ([M+H]⁺), ESI pos.

b)1-[(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]ethanone

To a solution of(4S)-7-chloro-6-(2,6-difluorophenyl)-8-(1-ethoxyvinyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(280 mg, 0.650 mmol) in 1,4-dioxane (7 mL) was added aqueoushydrochloric acid (2.0 M, 1.62 mL, 3.23 mmol). The mixture was stirredat room temperature for 0.5 h, before being diluted with dichloromethane(100 mL). The organic layer was washed with water (3×10 mL), aqueoussodium bicarbonate (3×50 mL) and brine (50 mL), then dried over sodiumsulfate and concentrated in vacuo. The residue was purified bypreparative HPLC (Boston Prime C18, 0.1% trifluoroacetic acid inwater/acetonitrile) and lyophilized to afford the title compound (220mg, 84%) which was obtained as a light yellow solid. MS: 401.1 ([M+H]⁺),ESI pos.

c)(4S)-7-chloro-8-(1,1-difluoroethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

To a solution1-[(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]ethanone(100 mg, 0.250 mmol) in dichloroethane (2 mL) was addeddiethylaminosulfur trifluoride (120.6 mg, 0.750 mmol) at 0° C. Themixture was stirred at room temperature for 24 h, before being pouredinto saturated aqueous sodium bicarbonate (20 mL). The mixture wasextracted with dichloromethane (2×50 mL). The combined organic extractswere washed with brine (30 mL), dried over sodium sulfate andconcentrated in vacuo. The residue was purified by preparative HPLC(Phenomenex Synergi C18, 0.1% trifluoroacetic acid inwater/acetonitrile) to afford the (−)-enantiopure (S)-title compound(20.1 mg, 18%) which was obtained as a white solid. MS: 423.0 ([M+H]⁺),ESI pos.

Example 94(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(6-methylpyrimidin-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing 6-methylpyrimidine-4-carbohydrazide was converted after chiralpurification into the (−)-enantiopure (S)-title compound (70.0 mg, 35%)which was obtained as a white solid. MS: 471.2 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESIpos.

Example 95(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-4-methyl-1-(2-methylpyrimidin-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing 2-methylpyrimidine-4-carbohydrazide was converted after chiralpurification into the (−)-enantiopure (S)-title compound (12.0 mg, 20%)which was obtained as a white solid. MS: 471.2 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESIpos.

Example 96(4S)-7,8-dichloro-6-(2,6-difluorophenyl)-1-(2,6-dimethylpyrimidin-4-yl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6,7-dichloro-5-(2,6-difluorophenyl)-3-methyl-1,3-dihydro-1,4-benzodiazepine-2-thioneusing 2,6-dimethylpyrimidine-4-carbohydrazide was converted after chiralpurification into the (−)-enantiopure (S)-title compound (66.8 mg, 44%)which was obtained as a white solid. MS: 485.1 ([{³⁵Cl, ³⁵Cl}M+H]⁺), ESIpos.

Example 97(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4,8-trimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

A mixture of(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(300 mg, 0.690 mmol), tetrakis (triphenylphosphine) palladium (0) (79.2mg, 0.070 mmol), trimethylaluminum (2.0 M in toluene, 0.51 mL, 1.03mmol) in N,N-dimethylformamide (6 mL) was heated to 70° C. After 16 h,the mixture was diluted with dichloromethane (30 mL). The organic layerwas washed with water (20 mL), brine (30 mL), dried over sodium sulfateand concentrated in vacuo. The residue was purified by preparative HPLC(Boston Prime, 0.1% trifluoroacetic acid in water/acetonitrile) andlyophilized to afford the (−)-enantiopure (S)-title compound (27.3 mg,58%) which was obtained as a white solid. MS: 373.2 ([M+H]⁺), ESI pos.

Example 98(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-ethyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a)(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepine-2-thione

In analogy to experiment of example 30 a,(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-one(building block T) was converted into the title compound (600 mg, 92%)which was obtained as a yellow solid. MS: 429.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺),431.1 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

b)(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-onehydrazone

A solution of(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepine-2-thione(500 mg, 1.16 mmol) and hydrazine hydrate (117 mg, 2.33 mmol) intetrahydrofuran (5 mL) was cooled to 15° C. and stirred for 1 h. Themixture was concentrated in vacuo to afford the title compound (450 mg,90%) as a light green foam. MS: 427.2 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 429.3([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

c)(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-ethyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

A solution of(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-ethyl-1,3-dihydro-1,4-benzodiazepin-2-onehydrazone (450 mg, 1.05 mmol) and triethyl orthoacetate (854 mg, 5.26mmol) in toluene (5 mL) was heated to 120° C. After 1 h, the reactionmixture was concentrated in vacuo. The residue was purified directly byflash column chromatography (dichloromethane/methanol 20:1) followed bychiral purification to afford the (−)-enantiopure (S)-title compound(400 mg, 82%) as a light yellow foam. MS: 451.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺),453.0 ([{⁸¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 99(4S)-7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a)(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-vinyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

To a solution of(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(3.0 g, 6.85 mmol) in ethanol (70 mL) was added potassiumvinyltrifluoroborate (1.85 g, 1.37 mmol), triethylamine (2.08 g, 20.56mmol), [1,1′-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.5g, 0.690 mmol). The reaction mixture was heated to 80° C. After 16 h,water (100 mL) was added and the reaction mixture was extracted withethyl acetate (2×100 mL). The combined organic extracts were washed withbrine (100 mL), dried over sodium sulfate, filtered and concentrated invacuo. The residue was purified by flash column chromatography(petroleum ether/ethyl acetate/ethanol 20:3:1 to 8:3:1) to afford thetitle compound (2.8 g, 88%) which was obtained as a brown solid. MS:385.1 ([M+H]⁺), ESI pos.

b)(4S)-7-chloro-6-(2,6-difluorophenyl-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-8-carbaldehyde

To a solution of(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-8-vinyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(2.8 g, 7.28 mmol) in acetone (56 mL) and water (14 mL) was added osmiumtetroxide (184.99 mg, 0.730 mmol). After 10 min stirring at roomtemperature, sodium periodate (3.1 g, 14.5 mmol) was added and themixture was stirred for further 1 h at room temperature. The reactionmixture was diluted with water (10 mL) and ethyl acetate (100 mL). Theorganic layer was washed with brine (2×50 mL), dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash column chromatography (silica, dichloromethane/methanol 200:1 to60:1) to afford the title compound (1.8 g, 47%) which was obtained as ayellow solid. MS: 387.1 ([M+H]⁺), ESI pos.

c)(4S)-7-chloro-8-(difluoromethyl)-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

To a solution of(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-8-carbaldehyde(1.8 g, 4.65 mmol) in dichloroethane (37.0 mL) was addeddiethylaminosulfur trifluoride (2.25 g, 14.0 mmol) at 0° C. Uponaddition, the reaction mixture was warmed up to room temperature andstirred for further 2 h. The reaction mixture was quenched by additionof saturated aqueous sodium bicarbonate (10 mL), then extracted withdichloromethane (2×30 mL). The combined organic extracts were washedwith brine (2×50 mL), filtered and concentrated in vacuo. The residuewas purified by preparative HPLC (Boston Prime C18, 0.1% trifluoroaceticacid in water/acetonitrile) and lyophilized to afford the(−)-enantiopure (S)-title compound (359 mg, 50%) which was obtained as awhite solid. MS: 409.1 ([M+H]⁺), ESI pos.

Example 100(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a)(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl-1,3-dihydro-1,4-benzodiazepine-2-thione

In analogy to experiment of example 30 a,(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-one(building block U) was converted into the title compound (1.2 g, 76%)which was obtained as a yellow solid. MS: 445.0 ([{⁷⁹Br, ³⁵Cl}M+H]⁺),447.1 ([{¹Br, ³⁵Cl or ⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

b)(3R)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl-1,3-dihydro-1,4-benzodiazepin-2-onehydrazone

In analogy to experiment of example 98 b,(3S)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepine-2-thionewas converted into the title compound (1.1 g, 96%) which was obtained asa yellow solid. MS: 443.1 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 445.1 ([{⁸¹Br, ³⁵Cl or⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

c)(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 98 c,(3R)-7-bromo-6-chloro-5-(2,6-difluorophenyl)-3-(methoxymethyl)-1,3-dihydro-1,4-benzodiazepin-2-onehydrazone was converted after chiral purification into the(−)-enantiopure (R)-title compound (68 mg, 6%) which was obtained as awhite solid. MS: 467.2 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 469.1 ([{⁸¹Br, ³⁵Cl or⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 101[(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanol

To a stirred suspension of(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(230.0 mg, 0.490 mmol) and sodium iodide (147.43 mg, 0.980 mmol) indichloromethane (3 mL) was added at −30° C. a solution of borontribromide (308.0 mg, 1.23 mmol) in dichloromethane (0.5 mL). Thereaction mixture was warmed up to room temperature and stirred forfurther 1 h, before being concentrated in vacuo. The residue waspurified by preparative HPLC (Phenomenex luna, 0.1% trifluoroacetic acidin water/acetonitrile) then SFC (Daicel Chiralpak AD-H, 0.1% ammonia inmethanol) to afford the (−)-enantiopure (R)-title compound (71 mg, 47%)as a white solid. MS: 453.2 ([{⁷⁹Br, ³⁵Cl}M+H]⁺), 455.2 ([{⁸¹Br, ³⁵Cl or⁷⁹Br, ³⁷Cl}M+H]⁺), ESI pos.

Example 102(4S)-7-chloro-6-(2,6-difluorophenyl)-8-iodo-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

To a mixture of(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(100 mg, 0.228 mmol), rac-trans-N1,N2-dimethylcyclohexane-1,2-diamine(35.3 μL, 0.228 mmol), sodium iodide (342 mg, 2.28 mmol) and copper(I)iodide (21.8 mg, 114 μmol) was added 1,4-dioxane (10 mL) under Argon.The resulting suspension was heated to 115° C. for 6 days. A furtheramount of sodium iodide (685 mg, 4.57 mmol) and copper(I) iodide (218mg, 1.14 mmol) were added and the reaction mixture was stirred forfurther 2 days. The mixture was diluted with ethyl acetate and theorganic layer was washed twice with aqueous ammonia, brine, dried oversodium sulfate and concentrated in vacuo. The crude material waspurified by flash column chromatography (silica, methanol indichloromethane 0-15%), followed by chiral HPLC (Chiracel OD; eluent:20% (ammonium acetate 0.1 mol in ethanol) in heptane) to afford the(−)-enantiopure (S)-title compound (41.2 mg, 37%) as a white solid. MS:485.0 ([M+H]⁺), ESI pos.

Example 103[(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanol

a)[(4S)-7-chloro-6-(2,6-difluorophenyl-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methoxy-triisopropyl-silane

In analogy to experiment of example 30 b,(3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thioneusing 2-triisopropylsilyloxyacetohydrazide was converted into the titlecompound (300 mg, 33%) which was obtained as a light yellow oil. MS:599.2 ([M+H]⁺), ESI pos.

b)[(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methanol

To a solution of[(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl]methoxy-triisopropyl-silane(200.0 mg, 0.270 mmol) in tetrahydrofuran (4 mL) was slowly added TBAF(1.0 M in tetrahydrofuran, 0.81 mL, 0.810 mmol). The mixture was stirredat room temperature for 1 h, before being concentrated in vacuo. Theresidue was purified by flash column chromatography(dichloromethane/methanol 50:1 to 20:1), followed by preparative HPLC(UniSil 3-100 C18 Ultra, 0.225% trifluoroacetic acid inwater/acetonitrile) and SFC separation (Daicel Chiralcel OJ, 0.1%ammonia in ethanol) to afford the (−)-enantiopure (S)-title compound(13.6 mg, 10%) as a white solid. MS: 443.0 ([M+H]⁺), ESI pos.

Example 105(4R)-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

To an oven-dried vial equipped with a magnetic stir bar and a Teflonseptum was added(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-(methoxymethyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(10 mg, 21.4 □mol), sodium carbonate (9.06 mg, 85.5 □mol), CuBr₂·2LiBr(4.28 μmol), Mes-Umemoto reagent (22 mg, 42.8 □mol),Ir[dFMeppy]₂-(4,4′-dCF₃bpy)PF₆ (56 μg, 0.0535 μmol) and (Me₃Si)₃SiOH(8.5 mg, 32.1 μmol). The vial was then degassed by alternativeevacuation and back filling with nitrogen, then degassed acetone (0.2mL) was added via syringe addition. The reaction mixture was stirred atroom temperature for 16 h under irradiation of a blue LED (Kessil lamp40 W, 420 nm). The vial was opened and the reaction mixture was filtereddirectly through a plug of celite. The filter cake was rinsed with ethylacetate (2.0 mL) and the filtrate concentrated in vacuo. The residue wasdissolved in ethyl acetate (20 mL) and washed with water and brine (3×15mL), dried over sodium sulfate, filtered and concentrated in vacuo. Thecrude material was purified by preparative HPLC (Gemini NX5Y, 0.1%formic acid in water/acetonitrile) to afford the (−)-enantiopure(R)-title compound (3 mg, 30%) as a white solid. MS: 457.2 ([M+H]⁺), ESIpos.

Example 106[(4R)-7-chloro-6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazlo[4,3-a][1,4]benzodiazepin-4-yl]methanol

In analogy to experiment of example 105,[(4R)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]methanolwas converted into the (−)-enantiopure (R)-title compound (9 mg, 31%)which was obtained as a white lyophilized powder. MS: 443.1 ([M+H]⁺),ESI pos.

Example 107(4S)-7-chloro-6-(2,6-difluorophenyl)-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 105,(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-4-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepinewas converted into the (−)-enantiopure (S)-title compound (1 mg, 10%)which was obtained as a white solid. MS: 413.2 ([M+H]⁺), ESI pos.

Example 108(4S)-7-chloro-6-(2,6-difluorophenyl)-1-ethyl-4-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,(3S)-6-chloro-5-(2,6-difluorophenyl)-3-methyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thioneusing propanehydrazide was converted after chiral purification into the(−)-enantiopure (S)-title compound (16.4 mg, 13%) which was obtained asa white solid. MS: 444.1 ([M+H]⁺), ESI pos.

Example 109(4S)-7-chloro-6-(2,6-difluorophenyl)-8-ethyl-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

To a solution of(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(120 mg, 0.274 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CH₂Cl₂ (4.5mg, 5.5 μmol) in dry tetrahydrofuran (1.2 mL) at 0° C. was addeddropwise diethylzinc (1.0 M in heptane, 0.823 mL, 0.823 mmol). Thereaction was allowed to warm to room temperature, before being heated to55° C. for 15 h. The reaction mixture was poured into water andextracted twice with ethyl acetate. The combined organic layers werewashed with water and brine, dried over sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified by preparativeHPLC (Gemini NX, 0.1% triethylamine in water/methanol), followed bychiral HPLC (Reprosil Chiral NR, 0.01 M ammonium acetate in ethanol,30%) to afford the (−)-enantiopure (S)-title compound (31.7 mg, 30%) asa white powder. MS: 387.3 ([M+H]⁺), ESI pos.

Reference Compounds RE-A8-bromo-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a) N-[2-(2,6-difluorobenzoyl)phenyl]acetamide

In analogy to experiment of building block A b,2-methyl-3,1-benzoxazin-4-one (CAS #525-76-8) was converted into thetitle compound (40 g, 80%) which was obtained as a light yellow solid.MS: 276.2 ([M+H]⁺), ESI pos.

b) (2-aminophenyl)-(2,6-difluorophenyl)methanone

In analogy to experiment of building block A c,N-[2-(2,6-difluorobenzoyl)phenyl]acetamide was converted into the titlecompound (19.5 g, 75%) which was obtained as a yellow solid. MS: 234.1([M+H]⁺), ESI pos.

c) (2-amino-5-bromo-phenyl)-(2,6-difluorophenyl)methanone

To a solution of (2-aminophenyl)-(2,6-difluorophenyl)methanone (5.00 g,21.4 mmol) in dichloromethane (50 mL) was added portionwiseN-bromosuccinimide (4.02 g, 22.51 mmol) at −15° C. The reaction mixturewas stirred at −15° C. for 1 h, till complete consumption of startingmaterial (as judged by LCMS analysis). The mixture was concentratedunder reduced pressure and the resulting residue purified by preparativeHPLC (Shim-pack C18, 0.225% trifluoroacetic acid in water/acetonitrile).The combined fractions were diluted with saturate aqueous sodiumbicarbonate and extracted with ethyl acetate (3×200 mL). The organicphase was washed with brine (2×100 mL), dried (Na₂SO₄) and concentratedin vacuo to afford the title compound (4.44 g, 66%) as a yellow solid.MS: 311.9 ([{⁷⁹Br}M+H]⁺), 314.0 ([{⁸¹Br}M+H]⁺), ESI pos.

d) 7-bromo-5-(2,6-difluorophenyl-1,3-dihydro-1,4-benzodiazepin-2-one

In analogy to experiment of building block A e,(2-amino-5-bromo-phenyl)-(2,6-difluorophenyl)methanone was convertedinto the title compound (300 mg, 13%) which was obtained as a yellowsolid. MS: 351.0 ([{⁷⁹Br}M+H]⁺), 353.0 ([{⁸¹Br}M+H]⁺), ESI pos.

e)7-bromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione

In analogy to experiment of example 30 a,7-bromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-one wasconverted into the title compound (310 mg, 92%) which was obtained as ayellow solid. The crude was used as such in the following step withoutfurther characterization.

f)8-bromo-6-(2,6-difluorophenyl-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 30 b,7-bromo-5-(2,6-difluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thioneusing acetohydrazide was converted into the title compound (5.1 mg, 4%)which was obtained as a white solid. MS: 389.0 ([{⁷⁹Br}M+H]⁺), 391.0([{⁸¹Br}M+H]⁺), ESI pos.

RE-B6-(2,6-difluorophenyl)-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

a) (2-amino-5-iodo-phenyl)-(2,6-difluorophenyl)methanone

To a solution of (2-aminophenyl)-(2,6-difluorophenyl)methanone (1.6 g,6.86 mmol) in DMF (15 mL) was added portionwise N-iodosuccinimide (1.62g, 7.2 mmol). The reaction mixture was stirred at 20° C. for 16 h,before being diluted with water (20 mL). The mixture was extracted withethyl acetate (3×20 mL), then the combined organic extracts were washedwith brine (2×10 mL), dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified by flash column chromatography (petroleumether/ethyl acetate, 10:1 to 5:1) to afford the title compound (2.0 g,81%) as a yellow solid. MS: 360.0 ([M+H]⁺), ESI pos.

b) 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one

In analogy to experiment of building block A e,(2-amino-5-iodo-phenyl)-(2,6-difluorophenyl)methanone was converted intothe title compound (650 mg, 12%) which was obtained as a yellow solid.MS: 399.0 ([M+H]⁺), ESI pos.

c) 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepine-2-thione

In analogy to experiment of example 30 a,5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-one wasconverted into the title compound (200 mg, 82%) which was obtained as ayellow solid. MS: 414.9 ([M+H]⁺), ESI pos.

d) 5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-onehydrazone

In analogy to experiment of example 64 a,5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepine-2-thionewas converted into the title compound (220 mg, 98%) which was obtainedas a yellow solid. MS: 413.0 ([M+H]⁺), ESI pos.

e)6-(2,6-difluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 98 c,5-(2,6-difluorophenyl)-7-iodo-1,3-dihydro-1,4-benzodiazepin-2-onehydrazone was converted into the title compound (150 mg, 64%) which wasobtained as a yellow solid. MS: 437.0 ([M+H]⁺), ESI pos.

f)6-(2,6-difluorophenyl-1-methyl-8-(trifluoromethyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of example 92 a,6-(2,6-difluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepinewas converted into the title compound (5 mg, 6%) which was obtained as awhite solid. MS: 379.0 ([M+H]⁺), ESI pos.

RE-C6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

To a stirred solution of8-bromo-6-(2,6-difluorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(30 mg, 0.08 mmol) in methanol (0.5 mL) was added 10 wt. % Pd/C (2.5 mg,2.4 μmol) and the resulting black suspension was purged by evacuationand then back filled with a stream of hydrogen (balloon) for threetimes. The mixture was stirred for 16 hours at room temperature underhydrogen atmosphere then filtered through a pad of dicalite. The filtercake was rinsed with methanol and the filtrate was concentrated invacuo. The residue was purified by preparative HPLC (PhenomenexGemini-NX C18, 0.1% trifluoroacetic acid in water/acetonitrile) followedby preparative TLC (silica, dichloromethane/methanol, 20:1) to obtainthe title compound (5 mg, 20%) as a white solid. MS: 276.2 ([M+H]⁺), ESIpos.

RE-D(4S)-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine

In analogy to experiment of reference compound RE-C,(4S)-8-bromo-7-chloro-6-(2,6-difluorophenyl)-1,4-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepinewas converted into the title compound (2 mg, 15%) which was obtained asa white solid. MS: 359.1 ([M+H]⁺), ESI pos.

1. A method for the treatment or prophylaxis of a GABA_(A) γ1 receptorrelated disease or condition, the method comprising administering to asubject in need thereof an effective amount of a compound selected fromthe group consisting of:

or a pharmaceutically acceptable salt[s] thereof.
 2. The method of claim1, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 3. The method of claim 1,wherein the disease or condition is autism spectrum disorder, Rettsyndrome, post-traumatic stress disorder or fragile-X disorder.
 4. Themethod of claim 1, wherein the disease or condition is autism spectrumdisorder.
 5. The method of claim 1, wherein the disease or condition isRett syndrome.
 6. The method of claim 1, wherein the disease orcondition is post-traumatic stress disorder.
 7. The method of claim 1,wherein the disease or condition is fragile-X disorder.
 8. The method ofclaim 2, wherein the disease or condition is autism spectrum disorder,Rett syndrome, post-traumatic stress disorder or fragile-X disorder. 9.The method of claim 2, wherein the disease or condition is autismspectrum disorder.
 10. The method of claim 2, wherein the disease orcondition is Rett syndrome.
 11. The method of claim 1, wherein thedisease or condition is post-traumatic stress disorder.
 12. The methodof claim 2, wherein the disease or condition is fragile-X disorder.